Down syndrome …

Neurobehavioral & Cognitive Disorders

Updated 06.05.2024
Released 10.29.1995
Expires For CME 06.05.2027

Down syndrome

Authors: Nicole Baumer MD MEd, George T Capone MD

See Contributor Disclosures

Editor: Ann Tilton MD

Down syndrome

In This Article

Quick Link

Introduction

Overview

Down syndrome, the most common genetic cause of intellectual disability, is caused by the presence of all or part of an extra chromosome 21 (198; 137). Down syndrome occurs in an estimated 8 in 10,000 live births (183). It is characterized by varying levels of intellectual disability, ranging from mild to severe cognitive impairment (138), as well as variable neurodevelopmental profiles, with significant heterogeneity and individual differences in cognition, language, and social and behavioral difficulties. In addition to congenital birth defects, persons with Down syndrome are at risk for acquired medical conditions during childhood, adolescence, and throughout adulthood, as well as premature onset of aging-related conditions beginning in the third to fourth decades of life. Some of the co-occurring medical conditions associated with Down syndrome have atypical presentations that require a high index of suspicion for diagnosis. Healthcare guidelines for persons with Down syndrome are designed to detect occult conditions in asymptomatic individuals and to guide physicians evaluating medically complex or difficult-to-diagnose patients. Successful recognition and treatment of medical conditions is paramount to managing patients with a decline in functional skills.

Key points

	• Down syndrome is caused by the presence of all or part of an extra chromosome 21 and occurs in an estimated 8 per 10,000 live births.
	• Down syndrome is the most common genetic cause of varying levels of intellectual disability, ranging from mild to severe cognitive impairment, as well as variable neurodevelopmental profiles.
	• There is significant heterogeneity and individual differences in cognition, language, and social abilities as well as a range of mental health disorders and behavioral difficulties in individuals with Down syndrome.
	• Healthcare guidelines for children and adults with Down syndrome exist to guide appropriate screening for co-occurring medical conditions.

Historical note and terminology

The first comprehensive description of this condition was provided by Dr. John Langdon Down in 1866. In his report of 1866, Down highlighted some of the salient aspects of the physical appearance and behavioral attributes of individuals with this syndrome.

Dr. John Langdon Down

In 1866, Dr. John Langdon Down provided the first comprehensive description of what is now known as Down syndrome. (Contributed by Dr. George Capone.)

The first illustrations in the medical literature of an individual with Down syndrome appeared in 1876 in a classic paper by Fraser and Mitchell, in which they provided marvelous illustrations of the face, foot, and skull (88). They were also the first to publish a pathologic description of the brain at autopsy.

Down syndrome patient (early illustration)

(Contributed by Dr. George Capone.)
Down syndrome patient (early illustration of face, foot, and skull)

These were among the first illustrations in medical literature depicting Down syndrome, presented in 1876 in a paper by Fraser and Mitchell. (Contributed by Dr. George Capone.)
Down syndrome patient (early illustration of brain)

This is an early illustration of the brain of a Down syndrome patient, presented by Fraser and Mitchell. (Contributed by Dr. George Capone.)

The term "Mongolian idiocy," or "Mongolism," was used widely throughout the latter part of the 19th and first half of the 20th century. The chromosomal etiology (trisomy 21) for Down syndrome has been known since 1959 (134). In 1961, sparked by the discovery 2 years earlier of trisomy 21 in persons with Down syndrome as well as by complaints from Chinese and Japanese scientific investigators, it was proposed that the term "Down syndrome" or "trisomy 21" be adopted to replace the inaccurate and anachronistic designation "Mongolism" (04). The complete DNA sequence of human chromosome 21 (long-arm) was determined in 2000 and is revolutionizing our genetic understanding of this condition (93; 114).

Clinical manifestations

Presentation and course

	• Individuals with Down syndrome have a higher risk of various medical, neurodevelopmental, and mental health conditions that manifest at different ages throughout the lifespan.
	• Physicians need to be aware of the variety of congenital and acquired medical problems as well as the neurodevelopmental and behavioral conditions associated with Down syndrome.

Development

The neurocognitive profile in Down syndrome is unique compared to other populations with intellectual disability and reflects underlying structural and functional neuroanatomic abnormalities and differences in brain development. Acquisition of early developmental milestones occurs in the typical progression, but at a slower rate, with wide variability. Cognitive neurodevelopment is impaired in nearly all individuals with Down syndrome, and most individuals with Down syndrome have cognitive impairment in the mild-moderate-severe range of intellectual disability, although some may have more profound impairments (48).

As expectations for language and cognitive growth increase during the second year of life, delays usually become apparent to both parents and professionals alike. Although it is difficult to determine what constitutes "typical" cognitive development, numerous studies have revealed a specific developmental trend in children with Down syndrome, and much work has focused on neurobehavioral and cognitive phenotypic characterization (15). A nonlinear rate of cognitive growth is often seen during the first decade of life (215; 41) and manifests as slowing in the rate of cognitive development with age. Reduced neuronal number in the cerebral cortex in conjunction with decreased synaptic number and density, as well as altered dendritic spine morphology, probably constitutes the major neurobiological substrate of cognitive impairment seen in these children.

Although global cognition is affected, developmental domains develop unevenly, with language abilities disproportionately impacted (01). These patterns of development lead to distinct neurocognitive and neurobehavioral profiles in Down syndrome. Developmental patterns in young children may predict future neurodevelopmental outcomes (83).

Like cognitive development, it is difficult to define what constitutes "typical" speech and language development in children with Down syndrome. There are large individual differences in the onset and complexity of spoken language (01). As a group, children with Down syndrome demonstrate greater deficits in verbal-linguistic skills relative to visual-spatial skills (196; 82), and many children demonstrate increasing deficits in verbal-linguistic skill with increasing chronological age (163). Asynchrony of language development has been well documented in this population. Language comprehension and production develop at significantly different rates, with production skills showing the greatest delays (164).

Neurodevelopmental and behavioral disorders: children and adolescents

Most children with Down syndrome do not have a coexisting psychiatric or behavioral disorder, and the available estimates of psychiatric comorbidity range from 20% to 40% (94; 100; 170; 46; 70; 36; 68). These estimates are greater compared to neurotypical children, but lower compared to children with similar levels of intellectual disability (94). When considering specific psychiatric disorders, it is useful to distinguish conditions with a prepubertal onset from those typically presenting during or after puberty, as these are biologically distinct periods that may impart vulnerability to specific types of psychiatric disorder (249; 55).

Attention-deficit/hyperactivity disorder (ADHD). ADHD is diagnosed by the presence of inattention, impulsivity, or motor hyperactivity disproportionate to mental age, resulting in significant academic or social impairment. Children with Down syndrome may have an increased risk of ADHD; the prevalence is reported to be about 10% to 44% (74; 72; 176). Although hyperactivity and impulsivity without inattention may be seen in young children with Down syndrome before 36 months (106), ADHD can be difficult to diagnose in children with Down syndrome as many symptoms may be developmentally congruent or part of the behavioral phenotype typically seen in children with Down syndrome (80). However, children with hyperactivity and impulsivity often engage in dangerous behavior and are at risk for elopement, wandering, and accidental injury, so these symptoms should not be easily dismissed. Careful consideration of co-occurring ADHD is necessary as it may require specialized treatment. Additionally, many children with Down syndrome have a component of hyperactivity-impulsivity or inattention in the presence of other neurobehavioral or psychiatric symptoms; therefore, the importance of looking at associated features is important because they will inevitably complicate both the diagnostic formulation and treatment approach (36). When diagnosing ADHD, it is important to gather collateral information from teachers or therapists to assess whether symptoms are evident in different settings. Treatment for ADHD is most effective when a multimodal approach is taken. Therefore, treatment should involve environmental modifications and accommodations, behavioral approaches, as well as pharmacological treatment. Although medication is one of the mainstays of treatment for ADHD, there have only been a few studies of medication use specifically in individuals with Down syndrome (34; 195).

Oppositional-defiant and disruptive behavior disorders. Oppositional defiant disorder (ODD) and disruptive behavior disorder (DBD) are related conditions distinguished by the severity, intensity, and pattern of negativistic, destructive, or aggressive behavior. Children with Down syndrome and oppositional defiant disorder or Down syndrome and disruptive behavior disorder often have comorbid ADHD, but not always. Taken together, ADHD-oppositional defiant disorder- disruptive behavior disorder form a continuum of disruptive behavior or conduct disturbance in childhood. Oppositional behavior may develop in temperamentally vulnerable toddlers without obvious hyperactivity-impulsivity before 36 months. Aggression in young children with Down syndrome is often impulsive or attention-seeking rather than malicious. Children with mild to moderate intellectual disability are quite capable of manipulating their caretakers through the use of socially motivated disruptive behavior. Thus, a longstanding pattern of undesirable behavior may become established. Routine inquiry about the child’s environment (setting – home versus school, consistency across environments) and known triggers (escape demands) should provide clues about the factors maintaining such disruptive behaviors.

Those children with a perseverative or inflexible cognitive style, anxiety, or mood dysregulation are often episodically oppositional, disruptive, or aggressive. Individuals who become increasingly difficult to manage with age may exhibit such features (18; 63; 242). These features are difficult to tease out during routine clinical observation, hence, our reliance on caretakers and teachers to provide a detailed qualitative description of these behaviors and triggering events.

Autism spectrum disorder. Autism spectrum disorder is a neurodevelopmental disorder characterized by difficulties with social interaction and communication and by certain characteristic patterns of behavior. The term “spectrum” refers to the wide range of symptoms that individuals can have, which varies greatly between individuals. Autism is more common in individuals with Down syndrome, although prevalence rates vary depending on diagnostic practices and study methodology (62; 168; 194).

Social communication is particularly impaired in children with both autism and down syndrome, and social disinterest, lack of sustained joint attention, and inability to communicate using gestures are symptoms that help distinguish autism spectrum disorder in children with Down syndrome. Behaviors often seen prior to 36 months include body rocking, arm/hand waving or flapping, dangling belts or strings, staring at lights, episodic ocular deviation, extreme food refusal, and unusual play with toys or other objects. Auditory processing impairments may cause the child to appear not to hear, and use of nonverbal gestural communication is often impaired.

In other children, symptoms suggesting an autistic spectrum disorder have a slow and insidious onset, appearing after 36 months with symptom intensification over many months or years. Preexisting repetitive behaviors, fearfulness, and sensory aversions may intensify. Peculiar sensory responding, fearfulness, anxiety, behavioral refusal, and sleep disturbance are often present (97; 118). Sometimes there is a distinct regression in speech, language, and social skills after 36 months (166). When frank developmental regression is well documented, even in the absence of clinical seizures, it may be useful to obtain overnight or extended EEG and a sleep study in the search for a treatable etiology. Neuroimaging and metabolic studies are rarely informative but may be considered.

Autism spectrum disorder may be difficult to diagnose in children with Down syndrome due to many overlapping symptoms in those with Down syndrome alone and those with combined Down syndrome and autism spectrum disorder. Recent work has been done to clarify these phenotypic differences (43; 83). Additionally, medical conditions that are common in Down syndrome can mimic or precipitate symptoms that are often seen in autism spectrum disorder, and some medical conditions may be more common in those with Down syndrome and autism spectrum disorder compared to autism spectrum disorder alone (223). Formal evaluation using standardized tests is important so that social communication skills can be considered in the context of the child’s overall developmental functioning. Some screening and diagnostic tools have been studied in Down syndrome and autism spectrum disorder and have been found to distinguish between those with Down syndrome who do and do not have co-occurring autism spectrum disorder, but this is an active area of research (16). The mainstays of treatment for autism spectrum disorder are educational and behavioral therapies, such as applied behavioral analysis, which is a data-driven approach to breaking down complex skills into smaller steps and can be an effective strategy for teaching skills and reducing maladaptive behaviors.

Stereotypic movement disorders. Stereotypic movement disorders can present similarly to autism spectrum disorders, and they are frequently confused with one another. When considered together, stereotypy movement disorders–autistic spectrum disorders align along a continuum of cognitive-language-social impairment and repetitive movements (37). Some children display unusual or atypical behaviors during infancy or the toddler years (31).

Children diagnosed with stereotypic movements are often regarded as “autistic-like” because of their frequently intense repetitive behaviors, unusual attention, and peculiar sensory features. However, when pressed many will demonstrate functional social communication and reciprocity, thus, excluding them from a label of autism spectrum disorder. Nevertheless, their symptom profile suggests a high burden of functional impairments similar to children who meet full diagnostic criteria for an autism spectrum disorder.

Psychiatric mental health disorders: adolescents and adults

By some estimates 20% to 30% of adults with Down syndrome have psychopathology (146; 152). Childhood maladaptive behavior and low levels of function are somewhat predictive of later psychopathology by young adulthood (153; 152).

Functional regression. There is an increasingly recognized phenomenon of unexplained regression occurring most commonly in adolescence that is sometimes referred to as unexplained regression in Down syndrome, Down syndrome disintegrative disorder, or Down syndrome regression disorder. This phenomenon involves a rather precipitous decline in previously stable social, language, cognitive-executive, and adaptive skills. It can accompany any of the major psychiatric disorders but appears most often in disorders with internalizing features, such as depression (02; 258; 165; 248; 206; 204). In some cases, regression appears to possibly be precipitated by a life stressor (208). The role of neuroimmune and inflammatory etiologies is an active area of investigation, with some recent success using immunological therapies in some patients (39; 112; 205). Functional adaptive skills may recover in some patients with successful pharmacologic treatment, including psychopharmacological or immunological treatment; however, the functional loss is permanent for others (50; 96; 02; 165). In rare instances, marked regression with functional decline occurs in the absence of any recognizable psychiatric disorder, except perhaps negative symptoms (180). Symptoms may manifest over weeks to months but are nonprogressive and appear relatively resistant to pharmacologic treatment. Catatonia is now established as a cause of functional regression in adolescents and young adults with Down syndrome (162). Its proper recognition is critical as symptoms may be responsive to benzodiazepines or electroconvulsive therapy (125; 98). For any cases of regression, other medical comorbidities, such as severe sleep apnea, seizures, or systemic illness, should also be sought. Thus, evaluation in a specialized center with expertise in this phenomenon may be important (207; 227).

Depression and depression-like disorders. Depression and depression-like disorders are common in adults with Down syndrome (47) but may not be more common when compared to adults with intellectual disability of other etiologies (146). Depressed mood, crying, anhedonia, decreased interest, psychomotor slowing, fatigue, appetite/weight change, and sleep disturbance are the most common criteria observed in Down syndrome with major depression. Poor concentration, reduced speech, and agitation are also common, whereas feelings of guilt or worthlessness are less often reported (49; 171). Previously independent self-care routines may deteriorate over time, requiring more frequent prompting by caretakers and additional time allowed for completion. Symptom exacerbation may occur in conjunction with menstrual cycles in vulnerable females. Increasing awareness of being different, lack of acceptance by peers, or negative life events resulting in bereavement may predate the onset of symptoms, which then evolve into a recognizable depression in vulnerable persons (65). Intrusive, obsessional thoughts and perseveration can be seen as an accompanying feature in major depression (171; 155). Subtle extrapyramidal symptoms, tremor, adventitial movements, tics, stuttering, and other vocalizations may also be present (44; 260).

In some Down syndrome individuals, depression is characterized less by mood disturbance (melancholy, crying, or irritability) and more by extreme affective blunting, apathy, cognitive-executive disorganization, psychomotor slowing, and reduced speech or mutism. Changes in appetite or sleep pattern may predate the onset of deterioration in mental status, and self-care skills may be greatly impacted. These internalizing features or “negative symptoms” raise the question of catatonia or a pseudodementia syndrome (33).

Depression is often misdiagnosed as dementia in middle-aged adults with Down syndrome. Routine evaluation should include testing thyroid, vitamin B12, and folate levels. Polysomnography should also be performed in subjects with or without obvious risk factors for obstructive sleep apnea (obesity, small-crowded oropharynx, macroglossia) who fail to respond to antidepressant medications (36). Because depression and sleep apnea often coexist, an incorrect diagnosis of dementia in a young adult may lead physicians and caretakers to abandon the search for effective treatments prematurely (32).

Rarely Down syndrome individuals present with hypomanic or mixed-mood states suggestive of a bipolar or atypical mood disorder (179; 178). There are often delays in making this diagnosis until irritability, agitation, or psychosis have steadily intensified over a period of years despite multiple medication trials.

Obsessive-compulsive disorders. Anxiety, phobias, panic episodes, obsessional thinking, motor slowing, or freezing and thought perseveration may be seen in the absence of significant mood disturbance in persons with Down syndrome (44). Obsessive thinking can be difficult to ascertain in persons with intellectual disability and limited speech but thought intrusion or verbal perseveration may represent a behavioral equivalent. Perseveration on past relationships or events, or a need to ask about upcoming scheduled activities, can be annoying to caretakers. Repetitive, compulsive acts, by its very nature, are easier to appreciate than obsessive thought (173; 181). Ordering and tidiness compulsions are quite common, especially rearranging personal belongings and opening/closing doors, cabinets, blinds, and light switches. Hoarding of seemingly trivial objects (clips, pens, or papers) and repetitive doodling or list-making is also observed. Agitation may occur when such seemingly insignificant objects are moved or appear out-of-place. If the compulsion to perform an action is so strong that anxiety or agitation typically ensues when the person is prohibited from carrying it out, then criteria for obsessive-compulsive disorder may be met.

Caretakers sometimes report the sudden appearance of compulsions, accompanied by changes in affect, mood, and sociability (173; 225). Life events such as changes at school or the workplace; loss of a friend, family member, or teacher; and physical-emotional trauma are commonly cited occurrences (79; 251). If physical or emotional trauma can be substantiated, a diagnosis of post-traumatic stress disorder may be considered. Sometimes, there is an intensification in preexisting compulsions accompanied by extreme motor slowing, freezing, or “obsessional slowness” (44), which raises concerns about catatonia or atypical parkinsonism.

Psychosis and psychotic-like disorders. The prevalence and diagnosis of psychosis-NOS and depression with psychotic features appears to be increased in adolescents and adults with Down syndrome compared to those with other forms of intellectual disability (43% vs. 13%), as is the prevalence of marked motoric slowing and mutism (17% vs. 0%). No differences were noted in the rates of depression or anxiety; however, the rates of bipolar (29% vs. 4%) and impulse control disorder (38% vs. 20%) were higher in those with other intellectual disabilities compared to Down syndrome (69).

It is important not to interpret all self-talk, or interaction with imaginary characters during times of stress or isolation, as prima facia evidence of psychosis (120). Psychosis often occurs within the setting of major depression in persons with Down syndrome but can manifest as the primary disorder (psychosis-NOS) without significant disturbance in mood (67; 69). Positive symptoms of psychosis such as paranoia, delusions, and hallucinations along with anxiety may be prominent features, or psychotic disorganization may coexist in the setting of profound apathy, abulia, motor slowing, and sleep disturbance (169; 171; 128; 02). Psychosis can also represent the manic phase of a bipolar disorder, which is infrequent, but should be considered when a family history is confirmed (178).

Medical conditions

The associated medical manifestations of Down syndrome are often categorized according to age epoch. In addition to the well-recognized phenotypic features that are characteristic of this condition, physicians need to be aware of the variety of congenital, acquired, and age-related medical conditions associated with Down syndrome (05).

Newborn: (0 to 1 month)

Neurologic. Neuromotor dysfunction, defined by generalized hypotonia and absent or diminished primitive and deep tendon reflexes, is characteristic of most newborns with Down syndrome (262).

Cardiac. Congenital heart disease occurs in 40% to 60% of newborns with Down syndrome. The most common cardiac lesions are atrioventricular canal (60%); isolated ventricular septal defect, atrial septal defect, or patent ductus arteriosus (30%); and tetralogy of Fallot (7%). Isolated congenital valve disease or coarctation of the aorta is seen occasionally (150). Cardiac defects are responsible for significant morbidity and mortality during the first 2 years of life (09), and recommendations are available focused on improving diagnosis of congenital heart disease and practices to optimize outcomes, such as type and timing of repair and perioperative considerations, as well as long-term monitoring needs (64).

Gastrointestinal. Anatomic gastrointestinal tract anomalies are seen in 6% to 12% of Down syndrome newborns, including duodenal stenosis or atresia (2.5%), imperforate anus (less than 1%), Hirschsprung disease (less than 1%), tracheoesophageal fistula esophageal atresia, bile duct atresia, malrotation, and pyloric stenosis. Physiologic complications such as oral motor dysfunction or gastroesophageal reflux are also commonly seen (25).

Ophthalmologic. Congenital cataracts are seen in about 2% to 4% of newborns with Down syndrome, which represents a 10-fold increase compared to the general population (197).

Endocrine. An increased incidence of congenital hypothyroidism due to absence or aplasia of the thyroid gland occurs in about 1% to 2% of newborns (54). A randomized clinical trial of thyroxine treatment in neonates with Down syndrome demonstrated a mild benefit in motor and mental development at 24 months (243).

Hematologic. A transient myeloproliferative disorder is sometimes seen in the first few months of life. Elevated peripheral blood leukocyte count with a predominance of "blasts" forms may make this condition difficult to distinguish from true congenital leukemia (250). Newborns with transient myeloproliferative disorder are at increased risk to develop acute megakaryoblastic leukemia (13). Approximately 3% to 10% of newborns with Down syndrome are diagnosed with transient myeloproliferative disorder (212). Most will not require treatment. However, treatment with exchange transfusion, pheresis, or cytarabine can improve survival for those with life-threatening symptoms, such as hyperviscosity and very high blast counts, or those with severe organomegaly (131; 91).

Infancy (1 to 12 months)

Neurologic. Some degree of neuromotor dysfunction (hypotonia, hyporeflexia, and diminished primitive reflexes) is characteristic of all infants with Down syndrome. Dysgenesis of the cerebral cortex and cerebellum, as well as delays in myelination during the first years of life, may constitute the primary neurologic substrate of neuromotor dysfunction. Delays in the acquisition of gross motor milestones are usually obvious to physicians and parents during the first 6 months of life. There is, however, considerable individual variation in the attainment of early motor milestones (264). A number of factors may account for this variability, including associated medical conditions (congenital heart disease, seizures, or hypothyroidism), degree of hypotonia, and delayed sensory-motor reaction times (216).

Seizures. The incidence of seizures during the first year of life is probably under 5%. Infantile spasms are the most common epilepsy syndrome in Down syndrome in the first year of life (224). Occasionally, tonic-clonic seizures, myoclonus, or febrile seizures are encountered (185). Infants with difficult-to-control infantile spasms or those in whom recognition and treatment is delayed frequently have a poorer developmental outcome (103; 73). Severe intellectual disability and autism-like behaviors are not an uncommon outcome, even in children who respond successfully to anticonvulsant medications (203).

Ophthalmologic. A number of ophthalmologic conditions may present during or shortly after the first year of life, including strabismus (23% to 44%), refractive errors (35% to 40%), nystagmus (5% to 30%), astigmatism (18% to 25%), amblyopia (10% to 12%), blepharitis (9% to 32%), keratoconus (5% to 8%), ptosis (5%), nasolacrimal duct obstruction (4% to 6%), and cataracts (4%) (197).

Infectious. Infants with Down syndrome are more susceptible to both viral and bacterial infections, particularly of the respiratory tract. Recurrent otitis media, sinusitis, and rhinitis are frequent problems, as are bronchiolitis and pneumonia. Lower respiratory tract infections may be a significant cause of morbidity and mortality during infancy (42). The increased predisposition to infections is probably the result of anatomic, immunologic, and cardiac factors. Respiratory infections tend to become less common with age and subsequent growth of craniofacial and respiratory structures (56).

Childhood (1 to 12 years)

Growth. All children and adolescents with Down syndrome demonstrate reduced linear growth rates between 2 and 4 standard deviations below the mean for the general population (53). More contemporary studies indicate improvements in weight gain and linear growth in young children, suggesting an association with improvements in medical care (265).

Endocrine. Disorders of thyroid function are particularly common in children with Down syndrome. There is a trend for thyroid-stimulating hormone values to increase and for thyroxine to decrease with advancing chronological age. Acquired hypothyroidism is seen in between 2% to 7% of children (54; 213). Both compensated (elevated thyroid-stimulating hormone or normal thyroxine) and uncompensated (elevated thyroid-stimulating hormone or decreased thyroxine) hypothyroidism are seen. A transient elevation in thyroid-stimulating hormone is sometimes noted in infants and children, which may be due to hypothalamic and pituitary dysregulation or end-organ insensitivity. This condition often resolves spontaneously. Compared to their unaffected siblings, total body fat and serum leptin levels are elevated in prepubertal children with Down syndrome (144).

Audiologic. There is a high incidence of hearing loss among children with this condition (10; 57). Some degree of conductive loss is found in up to 50% and is usually the result of otitis media, middle ear effusions, or impacted cerumen. Sensory-neural hearing loss, particularly for the higher frequencies, may be seen in up to 5% to 10% and may result from congenital anomaly of the inner ear or from cholesteatoma. A combination of conductive and sensory neural loss (mixed) is also seen in about 10% to 15% of children.

ENT/Pulmonary. Obstructive sleep apnea is noted in up to 31% of children with Down syndrome (226). One study reported abnormalities in overnight polysomnograms in 100% of Down syndrome subjects (hypoventilation 81%, obstructive sleep apnea 63%, and desaturation 56%) (147). More than 95% of non-obese children with Down syndrome and snoring were found to have obstructive sleep apnea on overnight polysomnograms (85). Symptoms of obstructive sleep apnea may include snoring, restless sleep, unusual sleep position, excessive mouth breathing, daytime somnolence, or behavioral changes. Factors that predispose Down syndrome children to obstructive sleep apnea include a small oral cavity with relative macroglossia, narrowing of the upper airway, hypotonia of the pharyngeal muscles, chronic rhinitis, obesity, and enlarged tonsils or adenoids. Adenotonsillectomy often results in a significant reduction in CO2 retention and the severity of both obstructive and central apneas (231). Even children who have undergone adenotonsillectomy may have persistent symptoms secondary to glossoptosis, hypopharyngeal collapse, recurrent adenoid tonsils, enlarged lingual tonsils, and macroglossia (66). Additional treatments include continuous positive airway pressure or surgical interventions.

Feeding-swallowing. Difficulties with feeding have long been recognized in infants and young children with Down syndrome, including food refusal, food selectivity by type or texture, oral motor delay, and dysphagia (84). The presence of a small-crowded oral cavity, gastro-esophageal or tracheo-laryngeal anomalies, oral motor hypotonia, and impaired sensory-motor skills are predisposing factors.

A pharyngeal phase type of swallow dysfunction has been well documented in Down syndrome (89; 175). High rates of both symptomatic and silent aspiration have been demonstrated in children with Down syndrome (175; 122). Many of these children had cardiac, gastrointestinal, pulmonary, and tracheal malformations requiring surgical repair in early childhood.

Hematologic. Numerous abnormalities or variation in red cell, white cell, and platelet lines have been reported in Down syndrome (92). Of greatest clinical significance is the increased risk in leukemia seen in Down syndrome children. Compared to typical children, acute megakaryoblastic leukemia is 500 times more likely to develop in children with Down syndrome under 3 years of age, whereas acute lymphocytic leukemia is 20 times more common in children with Down syndrome over 3 years of age (212). Overall, Down syndrome is associated with approximately 2% of all cases of acute leukemia in children (92; 87). There has been significant progress in identifying genes on chromosome 21 and potential mechanisms underlying the increased risk of leukemia in Down syndrome, as well as improvements in treatments (14). Children with Down syndrome are at risk for iron deficiency anemia, which is also harder to detect in Down syndrome due to macrocytosis. In addition to annual screening for anemia, annual screening for iron sufficiency and iron deficiency with specific iron studies has also been recommended (113; 26). Iron repletion should follow similar protocols as those for the general population.

Orthopedic. Children with Down syndrome are susceptible to subluxation of the hips, patella, and C-spine. Atlantoaxial subluxation may result in either acute trauma or slow chronic compression to the spinal cord (184; 45). Up to 14% of children show x-ray evidence of C1/C2 instability (atlantodens interval 3 to 5 mm) and are asymptomatic. Less than 1% of children demonstrate neurologic symptoms that may require treatment. Symptomatic children usually have an atlantodens interval greater than 8 mm. Symptoms may include brisk deep tendon reflexes with up-going plantar response, stumbling gait or inability to walk, loss of bowel or bladder control, and torticollis. Sensory findings are not usually present and are unreliable. In addition to C1/C2 instability, a higher incidence of atlanto-occipital instability and congenital anomalies of the craniovertebral junction and cervical spine have been reported (184; 90; 232; 160). Ligamentous laxity with or without accompanying vertebral anomaly (hypoplastic dens) is thought to predispose Down syndrome children to cervical subluxation.

Immunology. Immune dysfunction is proposed to account for the increased incidence of infections and frequent autoimmune phenomena in children with Down syndrome (172). Both B- and T-lymphocyte populations are often markedly reduced in young children (59). Several alterations of humoral immunity have been reported. Children under the age of 6 years appear to have a normal serum immunoglobulin profile. After 5 or 6 years, hypergammaglobulinemia of the IgG and IgA type is often seen. Serum IgG1 and IgG3 are usually elevated, whereas IgG2 and IgG4 are decreased. Serum IgM levels also start to decline during adolescence, becoming lower than normal by adulthood. Altered cellular immunity is also apparent, as evidenced by decreased numbers of lymphocytes and leukocytes. Evaluation of T-cell function indicates decreased mitogen and antigen-induced proliferation and interleukin-2 production.

Gastrointestinal. Celiac disease is more common and may or may not be associated with clinically significant gastrointestinal symptoms. Several studies have reported an increase prevalence of IgA-antigliadin antibody (non-specific), IgA-antiendomysium antibody, IgA-tissue transglutaminase antibody, and total serum IgA levels. Between 5% and 40% of children may have one or more abnormally high antibody levels, whereas the rate of intestinal biopsy confirmed celiac disease is closer to 7% (22; 40; 263). Screening for celiac disease is best done using combined IgA-antiendomysium antibody and IgA-tissue transglutaminase antibody determination (21), although IgA-tissue transglutaminase antibody appears to be the most specific (214).

Adolescence (13 to 18 years)

Growth. The adolescent growth spurt is less robust and typically occurs later compared to the general population (191). There is tendency toward excessive weight gain relative to height throughout childhood and adolescence. Final adult heights for males range between 140 and 160 cm, whereas the typical range for adult females is between 136 and 155 cm.

Reproductive endocrine. The onset and progression of puberty are the same or only slightly delayed for adolescent males with Down syndrome compared to the general population. Males typically show decreased penile length and testicular volume (119). Serum testosterone levels appear normal throughout puberty (186; 119). Reports of histologically abnormal testes, reduced sperm counts, and lack of mature sperm in males lead to the conclusion that most males with this condition are infertile. There is, however, one report of a male with Down syndrome who fathered a child; thus, questions about fertility remain unanswered (217).

The onset and duration of menstruation cycles are generally the same for females with Down syndrome compared to the general population (105). Reduced ovarian follicular size and number have been reported, and other histologic abnormalities have also been described (116).

Adulthood (18-40 years)

As longevity continues to increase greater numbers of adults with Down syndrome will live to be of advanced age (20). This presents ongoing challenges to the primary care physicians expected to manage an array of acquired, chronic, and age-related conditions (19).

Of the health conditions typically mentioned in adulthood, visual and hearing impairment, thyroid disease, obesity, sleep apnea, cardiopulmonary function, respiratory infections, seizure disorder, psychiatric disorders, and dementia are likely to remain the major considerations (78; 101; 35; 38; 207). Evidence-based clinical guidelines have been created to support the screening and diagnosis of nine different health conditions in adults with Down syndrome, resulting in 14 recommendations and four statements of good practice (234).

Growth. Excessive weight gain and obesity are common in younger adults with Down syndrome and may have a significant impact on coexisting medical conditions and quality of life (159).

Endocrine. There is an increasing risk for developing hypothyroidism with advancing age, as evidenced by higher thyroid-stimulating hormone and declining thyroxine levels (187). Persons with Down syndrome and hypothyroidism are also more likely to have elevated antithyroglobulin or antimicrosomal antibody titers, indicative of a Hashimoto-type thyroiditis.

Cardiac. The long-term outcome of congenital heart defects in adults is a topic of growing interest. One study employed prospective cardiac screening in a subset of participants from a residential setting who were ascertained retrospectively (247). Up to 17% of those patients had undiagnosed congenital heart defects in addition to the 16% with previously confirmed congenital heart defects (33%). Regurgitation of the mitral, aortic, and tricuspid valves was present in 75% of subjects. In patients with atrioventricular septal defect repair, left atrioventricular valve insufficiency and left ventricle outflow tract obstruction are the most frequently reported long-term complications requiring surgical repair (151). The largest study used a case-control design, including hospitalized participants with congenital heart defects with and without Down syndrome (12). The patients with Down syndrome and congenital heart defects had an increased prevalence of pulmonary hypertension, cyanosis, and secondary erythrocytosis compared to those without the condition. Among all of the hospitalized patients with congenital heart defects, mortality was higher for those with Down syndrome. Bacterial and aspiration pneumonia were exclusively associated with higher mortality in Down syndrome. Cardiac procedures, however, were less often performed in patients with Down syndrome.

Acquired mitral valve prolapse, tricuspid valve prolapse, and aortic regurgitation are frequently seen in early adulthood, irrespective of whether congenital heart disease was present at birth (104; 95). Typically, clinical symptoms are mild or absent. The actual prevalence of mitral valve prolapse in adults with Down syndrome is uncertain but may approach 60%. The prevalence of aortic regurgitation and tricuspid valve prolapse is estimated to be 11% and 17%, respectively.

Orthopedic. The only longitudinal study of atlantoaxial relationships over time indicates that the atlantoaxial (C1/C2) interval remains relatively stable (less than 1.5 mm change) over a 10- to 12-year period in most adults (188). Eight percent showed changes in C1/C2 interval measurement between 2 and 4 mm.

Reduction in bone mass (BMD) has been documented in middle-aged adults with Down syndrome. When adjusted for bone and body size, adults with Down syndrome demonstrated a lower volumetric BMD in lumbar spine and diminished bone strength relative to the loads that the femoral neck must bear (11). Factors related to reduced BMD may include hypogonadism, hypotonia, low muscle strength, reduced mobility, male gender, and reduced sunlight exposure (202; 108). Evidence suggests that diminished osteoblastic bone formation and inadequate accrual of bone mass, without differences in bone resorption, may be an underlying mechanism regardless of gender or other risk factors (156).

Cervical spondylosis and degenerative changes increase with age in adults with Down syndrome (03). Lower cervical spondylosis associated with osteophytic outgrowths and disc degeneration occurs at a higher rate than in the general population and may predispose Down syndrome adults to cervical myelopathy presenting as gait deterioration or loss of upper extremity use (174).

Audiologic. Persons with Down syndrome experience presbycusis or progressive bilateral sensorineural hearing during adulthood (24). Approximately two thirds of Down syndrome adults aged 35 years or older have a component of sensorineural hearing loss greater than 20 dB with relatively low rates (5%-10%) of isolated conductive hearing loss (81; 240). Almost half of all adults showed evidence of mixed conductive and sensorineural loss. Additionally, severity appears to increase with age, with about three fourths of older adults estimated to have moderate-profound hearing loss.

Ophthalmologic. Aging persons with Down syndrome have a high risk of developing visual impairment, cataracts, and keratoconus. Mild visual impairment is estimated to affect over 50% of older adults. Moderate vision impairment is seen in 21% whereas severe impairment affects 9% (240). Cataracts contribute to the high rates of visual impairment and are experienced by 30% to 68%, compared to the general population (17%) (115). In addition to the classic “senile cataracts,” there is an increased prevalence of “coronary cerulean cataracts,” which are flake-like lens opacities scattered throughout the peripheral cortex of the lens (142; 121). Surgical outcomes for cataract surgery in adults is generally good, but visual outcomes may be suboptimal due to other ocular abnormalities (135).

Finally, keratoconus (degeneration of the cornea) also contributes to vision problems. Keratoconus also increases in prevalence with age, occurring in 20% to 37% of elderly Down syndrome individuals compared to 11% in middle-aged patients with Down syndrome (115; 239). Corneal cross-linking under local anesthesia has now become the preferred treatment in select patients with promising results (222).

Dental. Severe periodontal disease consisting of gingivitis with loss of attachment and loss of alveolar bone is increased, whereas the prevalence of caries formation appears to be decreased in adults with Down syndrome (236). Tooth loss and other dental problems can result in problems chewing.

Gynecologic. Hypermenorrhea, menorrhagia, and premenstrual syndrome are reported to occur more frequently in adult females with Down syndrome (75). Menopause typically occurs earlier in women with Down syndrome. In one study, 87% of women with Down syndrome stopped menstruating by age 46 years and 100% had cessation by age 51 years (211). The median age of menopause in Down syndrome (47.1 years) is 2 years younger than in women with ID (49.3 years) and 4 years earlier than the average age of menopause in the general population (51.3 years) (157). Early menopause in women with Down syndrome has been associated with a 1.8-fold increased risk of dementia (hazard ratio 1.82) and with an increased risk of death (hazard ratio 2.05) (211; 51).

ENT/Pulmonary. It is now known that obstructive sleep apnea is more prevalent in adults with Down syndrome than previously thought. In the few studies that examine this issue, an extraordinarily high prevalence of hypopnea and apnea associated with desaturation were reported (07; 193). A relationship between apnea score and performance on cognitive testing was also noted (07). The risk for obstructive sleep apnea in adults is increased secondary to both upper airway anatomy and obesity. A study reported that 94% of adults with Down syndrome had abnormal polysomnograms, with 70% indicating severe obstructive sleep apnea [apnea-hypopnea index (AHI) over 30] (233). There was a clear correlation between BMI and AHI, but not for age and AHI or hypothyroidism and AHI. Patients presenting with lethargy, fatigue, mood changes, and cognitive decline, especially in early adulthood, should have overnight polysomnography as a routine part of their diagnostic evaluation (32).

The high rates of pneumonia in adults with Down syndrome may very well be related to micro-aspiration during feeding and drinking (19; 219). Clinical indicators of aspiration were seen in 70% of subjects in a young cohort of adults with Down syndrome, suggesting that they may be at a higher risk even at an early age (123).

Neurologic. Several studies have confirmed a bimodal peak in the prevalence of new-onset seizures in adults with Down syndrome (Evenhuis 1990; 185; 158). The first peak occurs between 20 and 30 years of age, with a second peak occurring around 45 years of age. Typically, partial complex and partial simple seizures are seen in the young adult–onset group and are not always associated with cognitive decline or diffuse EEG abnormalities.

Cerebrovascular disorders related to cerebrovascular pathology are also implicated in the age-related neurologic morbidity seen in adults with Down syndrome (252). The prevalence of myocardial infarction and cerebrovascular accident in Down syndrome is incompletely understood (124). In one large case-control study of hospitalized patients, adults with Down syndrome were at a higher risk of cerebrovascular events but at a lower risk of coronary events (males only), compared with age-matched individuals without Down syndrome (221). Another study found that despite an increased risk of vascular amyloidosis, adults with Down syndrome may enjoy relative protection from intracerebral hemorrhage compared to other high-risk groups (29). Furthermore, adults with Down syndrome may be relatively resistant to developing atherosclerosis compared to the general population, possibly due to reduced heart-type fatty acid binding protein (244).

Dysautonomia is very common as adults with Down syndrome generally have lower resting heart rates and blood pressures compared to the general population; furthermore, essential hypertension is uncommon (200). Chronic hypotension is often associated with other signs of autonomic dysfunction, including mottling or acrocyanosis of the peripheral extremities (27). In asymptomatic individuals, screening consists of monitoring heart rate and blood pressure for bradycardia and orthostatic hypotension. Symptomatic individuals will often have a history of syncope or pre-syncopal episodes, unusual spells, or falls. Preventive measures include maintenance of adequate hydration status, added salt to the diet, and caution on prolonged or sudden standing.

Elderly adults (older than 40 years)

Neurologic. Cervical spondylosis associated with osteophytic outgrowths, disc degeneration, and spinal canal stenosis can lead to the development of cervical myelopathy, which may present with gait disturbance, radicular symptoms, or loss of upper extremity use (174). In a study by van Allen and colleagues, 40% of elderly adults showed evidence of lower cervical spondylosis and degenerative changes (239). The neurologic consequences of these degenerative changes likely pose more of a neurologic threat than atlantoaxial instability among those of advanced age (03).

During adulthood, the risk of seizures increases with advancing age and may herald the onset of dementia. In adults over 50 years of age, between 24% to 46% have seizures (158; 154). Two studies have documented abnormal EEG findings in approximately 70% of elderly adults with Down syndrome independent of seizure status (Tangye 1979; 246). There was no apparent relationship between severity of EEG changes and dementia.

The seizures associated with dementia are often myoclonic jerks that may be prominent soon after awakening and are sometimes asymmetrical (61). Of the 18 patients that presented with myoclonic jerks, 14 (78%) also developed generalized tonic-clonic seizures. In older adults over 50 years of age, between 24% and 46% had seizures (158; 154). One study comparing Down syndrome individuals younger than 50 years of age to those individuals over 50 years of age documented increased use of anticonvulsant use in the older group (16% vs. 38%) (127).

No guidelines exist to aid in the selection of anticonvulsant therapy choices in elderly individuals with Down syndrome. However, a study by De Simone and colleagues found that valproic acid and levetiracetam seem to be most efficacious in treating myoclonic jerks and generalized tonic-clonic seizures (61). Gholipour found that a majority of patients with new-onset seizures achieve partial or complete seizure control (99).

Gait dyspraxia can be a subtle and early symptom of dementia that often leads to increased anxiety and fearfulness, which may impair functional ambulation prior to actual loss of walking ability (06).

Extrapyramidal symptoms are frequently associated with dementia in persons with Down syndrome. In one study, 36% of elderly individuals with Down syndrome who had dementia also had extrapyramidal symptoms, whereas none of the nondemented patients showed any evidence of extrapyramidal symptoms (246). Older studies estimated that 20% of demented middle-aged to elderly patients with Down syndrome displayed extrapyramidal symptoms (133). Other studies have reported both lower percentages (9%) and higher percentages (65%) (235). Possible mechanistic links between dementia and extrapyramidal symptoms include premature aging of substantia nigra neurons and subsequent decline in dopamine production (261). The contribution of basal ganglia calcifications to extrapyramidal symptoms has been examined, but these calcifications seem to be a near universal finding in adults with Down syndrome (254; 230); however, only a small percentage ever develop clinical extrapyramidal symptoms. Most often, extrapyramidal symptoms occur late in the course of dementia, though they are occasionally seen earlier. Extrapyramidal symptoms do not accompany all cases of dementia, and when present, they are usually of the rigid-hypokinetic variety (246). Symptoms may include tremor, rigidity in the extremities, shuffling gait, masked facies, orofacial dyskinesia, bradykinesia, and frontal release signs. Resting tremors and myoclonic jerks were not notable components of extrapyramidal symptoms in the Vieregge study. From a caregiver’s management perspective, extrapyramidal symptoms may be more impairing than the cognitive aspects of dementia. Gait can be markedly affected, requiring close supervision from caregivers. Extrapyramidal symptoms also interfere with a person’s ability to perform activities of daily living that require fine motor (dressing, toileting, grasping and holding utensils) and oral motor control (chewing, swallowing).

Dysphagia is also more common in adults with Down syndrome, although not well studied in elderly individuals (219). Beyond concerns for aspiration, swallowing dysfunction can also contribute to weight loss in elderly persons. It is likely that tooth loss and problems chewing also contribute to decreased oral intake. Symptoms of dysphagia may be subtle, and patients will rarely self-report difficulties with eating. However, choking, sputtering, gaging, or coughing are all concerning symptoms and should be further evaluated. Some patients will merely avoid eating or appear to have a loss of appetite. Even when swallowing dysfunction is not apparent, silent aspiration may be occurring.

Although obesity is common in young adults with Down syndrome, older adults often experience a decrease in BMI with advanced age compared to controls (181). In a study of 201 adults with Down syndrome, only 13 (7%) were found to be underweight; all were over 50 years of age (86). Indeed, one study suggests that unintentional weight loss in those over 36 years old may be related to the progression of Alzheimer-type pathology.

Alzheimer-type dementia. Despite the universal finding of Alzheimer-type neuropathologic changes in all individuals with Down syndrome by the fourth decade of life, the implications for the development of a clinical dementia syndrome are less clear. Once dementia symptoms are identified, the clinical symptoms progress rapidly in most subjects (245).

It appears that both the male gender and the apoE4 allele are associated with earlier onset of clinical dementia, whereas the apoE2 allele provides some protective effect (210).

Medications approved for the treatment of Alzheimer dementia in the general population have been found to have limited benefit in those with Down syndrome. A Cochrane analysis found insufficient evidence of benefit for treating people with Down syndrome and Alzheimer disease with acetylcholinesterase inhibitors (AChEI) or the NMDA receptor antagonist, memantine (136). An increase in behavioral symptoms was reported with donepezil. Eady and colleagues reported longer survival in those taking medications (donepezil), but the study group was younger and had other significant factors in their favor (71). Potential disease-modifying amyloid-lowering drugs are being tested in phase 2 trials for early-stage Alzheimer dementia (107; 241). None of the clinical trials of lecanemab or donanemab have included persons with Down syndrome, yet there is a need for such studies to address issues of safety and tolerability in this vulnerable population (189). A novel anti-amyloid vaccine has demonstrated acceptable safety, tolerability, and immunogenicity in a phase 1b randomized trial in adults with Down syndrome (190).

Elderly adults with Down syndrome without dementia demonstrate fewer and less severe maladaptive behaviors than those with early or mid-stage dementia. The maladaptive behaviors associated with progression into early stages of dementia may include aggression, fearfulness, sadness, sleep problems, and other regressive behaviors (237). Psychiatric symptoms are often apparent and may include delusions, hallucinations, and depression with associated appetite and sleep problems (238).

Longevity. Longevity has been increasing rapidly in the Down syndrome population since around 1970. In 2007, the median age (53 years) and the mean age (47.3 years) at death showed a 3.75-fold increase compared to 1970 (183). Further, there is a notable increase in the number of ageing adults between 35 to 60 years (born 1947-1972) who require expert medical care. Although longevity in Down syndrome adults is increasing overall, previous studies suggest that these increases have been substantially lower for some minority groups (259).

Mortality. The most significant medical disorders related to mortality are dementia, declining motor function, epilepsy, and respiratory infections (19; 51; 101). Approximately 13% of death certificates reviewed in New York in 2007 listed pneumonia due to aspiration or choking as the primary cause of death (266), and most bacterial pneumonias are likely linked to aspiration of pharyngeal contents. Another study looking at the relationship between hospitalization and mortality as a function of congenital heart disease in adults with and without Down syndrome found that those with Down syndrome/congenital heart disease were more likely to have hypothyroidism, dementia, heart failure, pulmonary hypertension, cyanosis, and secondary polycythemia. Individuals with Down syndrome/congenital heart disease also experienced higher in-hospital mortality and were less likely to undergo a cardiac procedure or surgery (12).

Prognosis and complications

A medical prognosis given during the newborn period should be determined on an individual basis, based on the presence or absence of specific medical conditions. Caution should be exercised in issuing an overly positive or negative developmental prognosis early in life because of the wide individual variation in neurodevelopmental outcome.

Biological basis

	• In individuals with Down syndrome, 90% to 95% result from full trisomy 21; 2% to 4% result from translocation; and 2% to 4% result from mosaicism.
	• The developmental expression of normal genes present in triplicate results in altered patterns of development and, ultimately, abnormal morphology and physiologic function.

Etiology and pathogenesis

Down syndrome most often results from complete trisomy of chromosome 21 due to nondisjunction during gamete formation (134). In about 95% of cases of trisomy 21, the nondisjunction is of maternal origin (08). Such cases of nondisjunction appear to occur "randomly" during meiosis, as the extra chromosome is not "inherited" per se. Rarely, nondisjunction will occur after fertilization is complete, resulting in two different cell lines. This condition is referred to as mosaicism because there exist one trisomic and one euploid cell line within the same embryo-fetus. A small number of cases result from either complete or partial translocation of chromosome 21 to another chromosome (usually in the G or D group). Some forms of translocation Down syndrome are associated with a familial pattern of inheritance (253). Overall, 90% to 95% of cases of Down syndrome result from full trisomy 21; 2% to 4% result from translocation; and 2% to 4% are the result of mosaicism (161; 117).

In Down syndrome, as in other trisomic conditions, the developmental expression of normal genes present in triplicate results in altered patterns of development and ultimately abnormal morphology and physiologic function (77; 30; 143). Chromosome 21, the smallest autosomes, contains about 35 million base pairs of DNA. The short arm (21p) contains multiple copies of genes coding for ribosomal RNA and a proximal region composed of highly repetitive DNA sequences. All of the other genes on chromosome 21 map to the long arm (21q). The entire DNA sequence for chromosome 21 was originally predicted to contain about 225 genes, although additional predictions based on mRNA transcript catalogues estimate approximately 550 possible genes (114; 192; 228).

To view the most recent catalogue of known genes mapping to chromosome 21, visit the Online Mendelian Inheritance in Man Web Site.

Neuropathology

Brain development. Brain size is often normal throughout gestation and the first 6 months of postnatal life before decelerating during the second half of the first year of postnatal life (209; 177). The brain in Down syndrome is said to have a characteristic morphologic appearance that permits it to be easily identified at autopsy. Decreased size and weight with foreshortening of the anterior-posterior diameter, flattening of the occiput, and narrowing of the superior temporal gyrus are most characteristic. Primary cortical gyri may appear wide, whereas secondary gyri are often poorly developed or absent with shallow sulci (58). The cerebellum and brainstem are often markedly reduced in size compared to forebrain structures (52). Dysplasia of the brain is probably best reflected by changes in head growth and circumference during the first few years of life (177). Detailed neuropathologic studies reveal a generalized hypocellularity of the brain. Reduction in neuronal number and density has been demonstrated for most regions examined (255). In the cerebral cortex, there is neuronal reduction in all cortical layers, with striking paucity of small interneurons from cortical layers II and IV (199). These interneurons use the neurotransmitter GABA and provide primary inhibitory influence to the pyramidal neurons. Reductions in this cell population may have particular significance for understanding the co-occurrence of spasms during infancy. Ultrastructural studies of pyramidal neurons from the cerebral cortex reveal abnormalities of dendritic arborization and reduced numbers of postsynaptic spines (149; 229; 17). Surviving spines are often abnormally long, thin, or irregular in contour and appearance (148). As would be predicted, reductions in synaptic density and surface area are also present (255). During the first year of life, decreased myelination is noted throughout the cerebral hemispheres, basal ganglia, cerebellum, and brainstem (256). After the first year, myelination delays primarily affect those fiber tracks with a late beginning and slow myelination cycle. The intracortical fibers and U-fibers of the frontal and temporal cortices are especially vulnerable.

Brain aging

Several important age-related changes in the brain have been described in association with Down syndrome. Basal ganglia calcification seems to be a near universal finding in individuals with Down syndrome, although its pathogenesis and clinical significance remain obscure (254; 230). Typically, the globus pallidus and putamen are affected. Using computerized tomography, Wisnewski demonstrated that 27% of individuals with Down syndrome of various ages showed basal ganglia calcification. In contrast, 100% of postmortem brains showed basal ganglia calcification on histopathologic examination, yet only 11% of these brains showed basal ganglia calcification when evaluated by CT prior to autopsy.

The neuropathologic stigmata of Alzheimer-type disease are another universal finding in Down syndrome. Possible factors influencing the pathogenesis include APP production and metabolism, inflammatory mechanisms, cholesterol metabolism, APOE genotype (140), and menopausal status (211; 51).

Middle-aged and elderly individuals develop senile plaques, neurofibrillary tangles, and granulovacuolar bodies that are virtually identical to the Alzheimer pathology seen in the general population (28; 76). Alzheimer-type neuropathologic changes are most pronounced throughout the cerebral cortex and limbic structures. Autopsy studies have convincingly demonstrated that senile plaques and neurofibrillary tangles are present in all individuals with Down syndrome by the fourth decade of life (257), with some individuals showing a much earlier onset (201). In addition to the histopathologic similarities, a similar pattern of neurochemical deficits is seen. Presynaptic markers for cholinergic, noradrenergic, and serotonergic markers are all reduced in the brains of aged individuals with Down syndrome (261; 102). These neurochemical changes appear to be caused by degeneration and cell loss of the cortical projection neurons arising from the nucleus basalis of Meynert (cholinergic), locus coeruleus (noradrenergic), and dorsal Raphae nuclei (serotonergic). Progressive degeneration and loss of neurons from these nuclei are associated with the appearance of senile plaques and neurofibrillary tangles within the cerebral cortex and hippocampus (Table 1) (145).

Table 1. Down Syndrome: Histopathology of Cortically Projecting Neurons

	I <30 years (n=2)	II 30 to 50 years (n=5)	III >50 years (n=15)
Temporal cortex
• Senile plaques • Neurofibrillary tangles • Cell number • Nucleolar volume	0 0 100% 100%	+ + 100% 100%	++++ ++++ 40% to 60% 70% to 80%
Nucleus basalis
• Cell number • Nucleolar volume	100% 100%	80% 100%	40% 80%
Locus coeruleus
• Cell number • Nucleolar volume	100% 100%	90% 90%	30% 90% to 95%
Dorsal raphae
• Cell number • Nucleolar volume	100% 100%	100% 95%	75% 75%
0 not present; + minimally present; ++++ abundant
Adapted from (145)

Diagnostic workup

• It is essential that a karyotype be performed to confirm the diagnosis of Down syndrome and to distinguish complete trisomy 21 from trisomy 21 mosaicism and trisomy 21 due to an unbalanced translocation, as this has implications for genetic counseling and recurrence risk.

Diagnosis. A presumptive diagnosis of Down syndrome is usually made by the physician or hospital staff shortly after birth. The 10 most common physical features that may aid in diagnosis were outlined by Hall (Table 2) (109). No single phenotypic finding is diagnostically significant; rather, it is the association of three or more of these features together that warrants suspicion. Fluorescence in situ hybridization (FISH) may be used for rapid diagnosis of Down syndrome in the newborn period. However, a definitive diagnosis requires cytogenetic testing (karyotype) to confirm either complete or partial trisomy 21 or a translocation.

Table 2. Diagnostic Features of Down Syndrome in the Newborn Period

• Flat facial profile • Poor Moro reflex • Hypotonia • Hyper flexible joints • Excessive skin on neck • Slanted palpebral fissures • Pelvic dysplasia • Anomalous auricles • Dysplastic midphalanx of the fifth finger • Single palmar crease • Down syndrome newborns who demonstrate at least four features • Down syndrome newborns who demonstrate six or more features	90% 85% 80% 80% 80% 80% 70% 60% 60% 45% 100% 90%
Adapted from (109)

The karyotype performed on blood lymphocytes or skin fibroblasts is mandatory to confirm the diagnosis of Down syndrome, even in cases where the phenotypic appearance is obvious. It is critical for purposes of genetic counseling to distinguish complete trisomy 21 from trisomy 21 mosaicism and trisomy 21 due to an unbalanced translocation.

Management

	• Preventative screening is recommended for many of the medical conditions associated with Down syndrome. Age-based checklists of medical screening recommendations exist to guide families and healthcare professionals.
	• Clinical management for specific medical conditions is often the same in individuals with Down syndrome compared to those without Down syndrome.

Clinical management of specific medical conditions is generally no different in individuals with Down syndrome compared to others in the general population. Because of the high incidence of certain conditions, preventive medical screening of asymptomatic individuals at regular intervals is recommended (Table 3).

Table 3. Down Syndrome Medical Checklist

Infancy (birth to 12 months)
	• Karyotype confirmation and genetic counseling, newborn period • Cardiac evaluation and echocardiogram, newborn period • Confirm red reflex, newborn period • Ophthalmology evaluation, by 10 to 12 months • Check thyroid screen, newborn period • Complete blood-count, newborn period • Subacute bacterial endocarditis prophylaxis in susceptible children • Consider influenza vaccine • Consider RSV prophylaxis • Monitor cardiac, gastrointestinal, and neurodevelopmental function • Obtain a swallow study when oral hypotonia is severe, or when feeding problems or recurrent respiratory infections occur • Audiology (hearing) evaluation, by 6 months • Compile a medical information log • Appointment at a Down syndrome clinic
Childhood (1 to 12 years)
	• Recheck thyroid function tests, yearly • Complete blood count and iron studies or ferritin and CRP level annually • Continue subacute bacterial endocarditis prophylaxis in susceptible children • Consider influenza and pneumococcal vaccine • Monitor ENT, cardiac, gastrointestinal, sleep, behavior, and neurodevelopmental function • Obtain an overnight sleep study (r/o OSA) if symptoms or anatomical risk factors are present • Consider antibiotic prophylaxis, allergies, ventilation tubes, and ENT consultation • Recheck hearing at least annually • Ophthalmology (vision) evaluation, by 1 year • Cervical spine x-ray if myelopathic symptoms are present. Lateral neck (neutral, flexion, and extension views). Measure atlanto-dens interval (C1-C2) and neural canal width. • Regular physical exercise and recreational programs • Continue medical information log • Appointment at a Down syndrome clinic
Adolescence (12 to 18 years)
	• Echocardiogram for mitral valve prolapse and aortic regurgitation, if new murmur is present • Continue subacute bacterial endocarditis prophylaxis in susceptible individuals • Consider influenza vaccine • Monitor sleep, behavior, and mental health function • Recheck thyroid function tests, yearly • Continue annual anemia and iron insufficiency/deficiency screening • Recheck hearing, at least every 2 years • Recheck vision, at least every 2 to 3 years • Cervical spine x-ray if myelopathic symptoms are present. Lateral neck (neutral, flexion, and extension views). Measure atlanto-dens interval (C1-C2) and neural canal width. • Repeat polysomnography if risk-factors or symptoms are present despite previous T & A • Menstruating females: consider gynecology evaluation (pelvic examination or ultrasound) as required • Dental evaluation, twice yearly • Regular physical exercise and recreational programs • Continue medical information log • Appointment at a Down syndrome clinic
Adulthood (18 to 40 years)
	• Echocardiogram for mitral valve prolapse and aortic regurgitation if new murmur is present • Monitor for syncope from bradycardia and low resting blood pressure • Consider influenza vaccine • Monitor sleep, behavior, and mental health • Recheck thyroid function tests, yearly • Monitor Vitamin D, calcium, and endocrine studies • Recheck hearing, at least every 2 years • Recheck vision, at least every 2 to 3 years • Cervical spine x-ray if myelopathic symptoms are present. Lateral neck (neutral, flexion, and extension views). Measure atlanto-dens interval (C1-C2) and neural canal width. • Obtain overnight sleep study (r/o OSA) if symptoms or anatomical risk factors are present, despite previous T & A • Menstruating females: consider gynecology evaluation (pelvic exam or ultrasound) as required • Dental evaluation, twice yearly • Regular physical exercise and recreational programs • Appointment at a Down syndrome clinic
Senescent adults (older than 40 years)
	• As above • Cervical spine x-ray and MRI if myelopathic or radicular symptoms present • Monitor Vitamin D, calcium • Maintain high vigilance for cognitive decline, behavior changes, gait deterioration, seizures, and dysphagia • Monitor safety during ambulation, feeding, bathing, and toileting • Arrange in-home support for caretakers as required
Adapted from (05; 220; 126; 234; 26)

Special considerations

Pregnancy

There are at least 31 reported cases of pregnancy in females with Down syndrome. Approximately one-third of offspring also have trisomy 21, another one-third have major malformations or intellectual disability, and one-third appear to be normal (23). An increased rate of prematurity is also seen.

Anesthesia

The cholinergic antagonist atropine has been reported to result in greater cardio-acceleration in adults with Down syndrome compared to controls (111). This needs to be considered whenever atropine is being given as a preanesthetic agent. A review of 100 patients with Down syndrome requiring general anesthesia for surgical procedures revealed no significant differences with inhaled anesthetics compared to normal children (132).

There are several reports of spinal cord compression and narrowing of the neural canal intraoperatively in children with Down syndrome (132; 60). In children over 2 years of age, C-spine films in neutral, flexion, and extension views should be obtained prior to general anesthesia in order to determine the propensity for C1-C2 subluxation and spinal canal narrowing associated with hyperextension of the neck. In children under 2 years, x-rays may not be informative. It is strongly recommended that anesthesiologists use caution when manipulating the head and neck at the time of intubation and throughout the intraoperative period in all persons with Down syndrome.

There are no reports regarding the use of agents for conscious sedation in Down syndrome; however, it is mandatory that all patients be carefully screened for a history of obstructive sleep apnea prior to administration of hypnotics or sedatives because hypoventilation may occur. The physician or nurse anesthetist should be prepared to intervene in such cases by repositioning the head and neck or by supplying supplemental oxygen.

Drug discovery and clinical trials

Cognitive function in youth. A safety and efficacy study of donepezil for cognitive function in older children with Down syndrome (10 to 17 years of age) has been published (129). In the largest random controlled trial of its kind involving children with Down syndrome, 129 subjects received either placebo or donepezil at 2.5 mg starting dose, which was escalated in 2.5 mg increments every 14 days until reaching 10 mg. Using the Vineland-II Adaptive Behavior Scales (VABS-II) Parent-Caregiver Rating Form (PCRF) as the primary outcome, improvement in both treatment and placebo groups was observed. Given the brevity of the trial, and the need for re-test, a practice-effect may have contributed to the improvements observed. Average daily dosing was 5.0 mg in the donepezil group and 5.6 mg in the placebo group, with greater than 90% compliance in both groups. The most common adverse events in the treatment group resulting from expected cholinergic overstimulation included diarrhea (12.5%) and vomiting (6.3). The majority of adverse events were mild or transient, with no serious adverse events reported. Only one subject receiving donepezil discontinued the study because of moderately disturbing urinary retention.

Cognitive therapies for dementia. Reports from several small clinical trials using acetylcholinesterase inhibitors in elderly persons with Down syndrome and clinical signs of dementia began to appear about 14 years ago (141; 180). Initially, mild improvement or slowing in the rate of cognitive deterioration was observed over a 3- to 6-month period in treated subjects. Within a matter of several years, randomized clinical trials were being conducted as joint investigator-initiated, industry-sponsored research. A study was designed to measure the safety and efficacy of donepezil on cognitive function in young adults with Down syndrome (18 to 35 years of age); a 12-week, double-blind, placebo-controlled trial was conducted in which 121 subjects received placebo or donepezil at 5 mg for 6 weeks and 10 mg for the remaining 6 weeks (130). Using the Severe Impairment Battery Scales (SIB) as the primary outcome, significant improvement on SIB score was noted in both groups after 12 weeks of the double-blind phase. The Vineland Adaptive Behavior Scales (VABS) captured significant improvement only in donepezil-treated subjects during the same period. Of the 121 subjects, 87 continued their participation for another 12 weeks in an open-label extension study. Those subjects previously on placebo who then received donepezil showed an improvement in SIB scores, whereas SIB scores for subjects previously on donepezil who continued on donepezil remained stable. Adverse events were more likely in donepezil-treated subjects in both the double-blind and open-label phases. No deaths or serious life-threatening events were reported in either group. Donepezil-treated subjects reported abdominal pain, nausea, vomiting, and insomnia at twice the rate of the placebo group. Most adverse effects were transient and only mildly or moderately impairing.

A study designed to measure the safety and efficacy of antioxidant supplementation on cognitive function in adults with Down syndrome over 40 years of age has been completed (139). This randomized, double-blind, placebo-controlled trial was conducted on 53 subjects receiving either placebo or antioxidant supplements (900 IU alpha-tocopherol, 200 mg ascorbic acid and 600 mg of alpha-lipoic acid) over a 2-year treatment period. Only 31 of the original 53 (58%) participants completed the study. No improvement or stabilization in cognitive function was observed using the Severe Impairment Battery Scales (SIB) as the primary outcome measure.

A novel NMDA glutamate receptor partial-antagonist memantine was examined for safety and efficacy in adults over 40 years of age (110). A randomized, double-blind, placebo-controlled trial was conducted on 163 subjects receiving either memantine or placebo for 52 weeks. Both groups declined on measures of cognitive and adaptive function using the Down’s syndrome Attention, Memory and Executive Function Scales (DAMES) and the Adaptive Behavior Scale (ABS). After adjustment for baseline scores, no group differences in the rate of decline were observed. Serious adverse events were also observed in both groups.

Media

References

01: Abbeduto L, Warren SF, Conners FA. Language development in Down syndrome: from the prelinguistic period to the acquisition of literacy. Ment Retard Dev Disabil Res Rev 2007;13(3), 247-61. PMID 17910087
02: Akahoshi K, Matsuda H, Funahashi M, Hanaoka T, Suzuki Y. Acute neuropsychiatric disorders in adolescents and young adults with Down syndrome: Japanese case reports. Neuropsychiatr Dis Treat 2012;8:339-45. PMID 22888254
03: Ali FE, Al-Bustan MA, Al-Busairi WA, Al-Mulla FA, Esbaita EY. Cervical spine abnormalities associated with Down syndrome. Int Orthop 2006;30(4):284-9. PMID 16525818
04: Allen G, Benda CE, Book JA, et al. Mongolism. Lancet 1961:775. PMID 17948460
05: American Academy of Pediatrics. Health supervision for children with Down syndrome. Pediatrics 2011;128;393-406. PMID 21788214
06: Anderson-Mooney AJ, Schmitt FA, Head E, Lott IT, Heilman KM. Gait dyspraxia as a clinical marker of cognitive decline in Down syndrome: a review of theory and proposed mechanism. Brain Cogn 2016;104;48-57. PMID 26930369
07: Andreou G, Galanopoulou C, Gourgoulianis K, Karapetsas A, Molyvdas P. Cognitive status in Down syndrome individuals with sleep disordered breathing deficits. Brain Cogn 2002:50(1):145-9. PMID 12372360
08: Antonarakis S. Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. N Engl J Med 1991;324:872-6. PMID 1825697
09: Baird PA, Sadovnick AD. Life expectancy in Down syndrome. J Pediatr 1987;110:849-54. PMID 2953876
10: Balkany TJ, Downs MP, Jafek BW, Krajicek MJ. Hearing loss in Down's syndrome. Clin Pediatr 1979;18(2):116-8. PMID 153815
11: Baptista F, Varela A, Sardinha LB. Bone mineral mass in males and females with and without Down syndrome. Osteoporosis Int 2005;16(4):380-8. PMID 1536569
12: Baraona F, Gurvitz M, Landzberg MJ, Opotowsky AR. Hospitalizations and mortality in the United States for adults with Down syndrome and congenital heart disease. Am J Cardiol 2013;111(7):1046-51. PMID 23332593
13: Barnett P, Clark A, Garson O. Acute nonlymphocytic leukemia after transient myeloproliferative disorder in a patient with Down syndrome. Med Pediatr Oncol 1990;18:347-53. PMID 2142749
14: Baruchel A, Bourquin J, Crispino J, et al. Down syndrome and leukemia: from basic mechanisms to clinical advances. Haematologica 2023;108(10):2570-81. PMID 37439336
15: Baumer NT, O'Neill ME. Neurological and neurodevelopmental manifestations in children and adolescents with Down syndrome. International Review of Research in Developmental Disabilities 2022;63:187-246.
16: Baumer NT, Pawlowski KG, Zhang B, Sideridis G. Validation of factor structure of the neurodevelopmental parent report for outcome monitoring in down syndrome: confirmatory factor analysis. Front Psychiatry 2024;15:1293937. PMID 38505792
17: Becker LE, Armstrong DL, Chan F. Dendritic atrophy in children with Down's syndrome. Ann Neurol 1986;20:520-6. PMID 2947535
18: Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 1991;148(5):564-77. PMID 2018156
19: Bittles A, Bower C, Hussain R, Glasson E. The four ages of Down syndrome. Eur J Pub Health 2007;17(2)221-5. PMID 16857692
20: Bittles AH, Glasson EJ. Clinical, social, and ethical implications of changing life expectancy in Down syndrome. Dev Med Child Neurol 2004;46(4):282-6. PMID 15077706
21: Bonamico M. Which is the best screening test for celiac disease in Down syndrome children. J Pediatr Gastroenterol Nutr 2005:40:125-7. PMID 15699683
22: Bonamico M, Rastore-Quartino A, Mariani P, et al. Down syndrome and coeliac disease: usefulness of antigliadin and antiendomysium antibodies. Acta Paediatr 1996;85:1503-5. PMID 9001668
23: Bovicelli L, Orsini LF, Rizzo N, Montacuti V, Bacchetta M. Reproduction in Down syndrome. Obstet Gynecol 1982;59(6 Suppl):13S-7S. PMID 6211644
24: Buchanan LH. Early onset of presbyacusis in Down syndrome. Scand Audiol 1990;19:103-10. PMID 2142538
25: Buchin PJ, Levy JS, Schullinger JN. Down's syndrome and the gastrointestinal tract. J Clin Gastroenterol 1986;8(2):111-4. PMID 2943789
26: Bull MJ, Trotter T, Santoro SL, et al. Health supervision for children and adolescents with Down syndrome. Pediatrics 2022;149(5):e2022057010. PMID 35490285
27: Bunsawat K, Baynard T. Cardiac autonomic modulation and blood pressure responses to isometric handgrip and submaximal cycling exercise in individuals with Down syndrome. Clin Auton Res 2016;26(4):253-60. PMID 27165540
28: Burger PC, Vogel S. The development of the pathologic changes of Alzheimer's disease in patients with Down's syndrome. Am J Pathol 1973;73:457-76. PMID 4271339
29: Buss L, Fisher E, Hardy J, et al. Intracerebral haemorrhage in Down syndrome: protected or predisposed? F1000Res 2016;5;pii:F1000 Faculty Rev-876. PMID 27239286
30: Capone G. Down syndrome: advances in molecular biology and the neurosciences. J Dev Behav Pediatr 2001;22(1):40-59. PMID 11265922
31: Capone G. Down syndrome and autistic spectrum disorders. In: Down syndrome: visions of the 21st century. Cohen W, Madnick M, editors. New York: John Wiley & Sons Inc, 2002.
32: Capone G, Aidikoff J, Taylor K, Rykiel N. Adolescents and young adults with Down syndrome presenting to a medical clinic with depression: co-morbid obstructive sleep apnea. Am J Med Genet 2013;161(9):2188-96. PMID 23913657
33: Capone GT, Aidikoff JM, Goyal P. Adolescents and young adults with Down syndrome presenting to a medical clinic with depression: phenomenology and characterization using the Reiss Scales and Aberrant Behavior Checklist. Journal of Mental Health Research in Intellectual Disabilities 2011;4:244-64.**
34: Capone GT, Brecher L, Bay M. Guanfacine use in children with Down syndrome and comorbid attention-deficit hyperactivity disorder (ADHD) with disruptive behaviors. J Child Neurol 2016;31(8):957-64. PMID 26936058
35: Capone GT, Chicoine B, Bulova P, et al. Co-occurring medical conditions in adults with Down syndrome: a systematic review toward the development of health care guidelines. Am J Med Genet A 2018;176(1):116-33. PMID 29130597
36: Capone G, Goyal P, Ares W, Lannigan E. Neurobehavioral disorders in children, adolescents, and young adults with Down syndrome. Am J Med Genet C Semin Med Genet 2006;142(3):158-72. PMID 16838318
37: Capone G, Grados M, Kaufmann W, Bernad-Ripoll S, Jewell A. Down syndrome and co-morbid autism-spectrum disorder: characterization using the aberrant behavior checklist. Am J Medi Gen 2005;134A(4):373-80. PMID 15759262
38: Capone G, Stephens M, Santoro S, et al. Co-occurring medical conditions in adults with Down syndrome: a systematic review toward the development of health care guidelines. Part II. Am J Med Genet A 2020;182(7):1832-45. PMID 32338447
39: Cardinale KM, Bocharnikov A, Hart SJ, et al. Immunotherapy in selected patients with Down syndrome disintegrative disorder. Dev Med Child Neurol 2019;61(7):847-51. PMID 30548468
40: Carlsson A, Axelsson I, Borulf S, et al. Prevalence of IgA-Antigliadin antibodies and IgA-Antiendomysium antibodies related to celiac disease in children with Down syndrome. Pediatrics 1998;101(2):272-5. PMID 9445503
41: Carr J. Six weeks to twenty-one years old: a longitudinal study of children with Down's syndrome and their families. J Child Psychol Psychiatry 1988;29:407-31. PMID 2975288
42: Chaney RH, Eyman RK, Miller CR. The relationship of congenital heart disease and respiratory infection mortality in patients with Down's syndrome. J Ment Defic Res 1985;29(Pt 1):23-7. PMID 3159899
43: Channell MM, Hahn LJ, Rosser TC, et al. Characteristics associated with autism spectrum disorder risk in individuals with Down syndrome. J Autism Dev Disord 2019;49(9):3543-56. PMID 31124029
44: Charlot L, Fox S, Friedlander R. Obsessional slowness in Down's syndrome. J Intellect Disabil Res 2002;46(6):517-24. PMID 12354323
45: Chaudhry V, Sturgeon C, Gates AJ, Myers G. Symptomatic atlantoaxial dislocation in Down syndrome. Ann Neurol 1987;21:606-9. PMID 2955739
46: Coe DA, Matson JL, Russell DW, Slifer KJ, Capone GT, Baglio C, Stallings S. Behavior problems of children with Down syndrome and life events. J Autism Dev Disord 1999;29(2):149-56. PMID 10382135
47: Collacott RA, Cooper S, McGrother C. Differential rates of psychiatric disorders in adults with Down's syndrome compared with other mentally handicapped adults. Br J Psychiatry 1992;161:671-4. PMID 1422617
48: Contestabile A, Benfenati F, Gasparini L. Communication breaks-Down: from neurodevelopment defects to cognitive disabilities in Down syndrome. Prog Neurobiol 2010;91(1):1-22. PMID 20097253
49: Cooper SA, Collacott RA. Clinical features and diagnostic criteria of depression in Down's syndrome. BR J Psychiatry 1994;165(3):399-403. PMID 7994516
50: Cooper SA, Duggirala C, Collacott RA. Adaptive behaviour after schizophrenia in people with Down's syndrome. J Omte;;ect Disabil Res 1995;39(Pt 3):201-4. PMID 7640490
51: Coppus AM, Evenhuis HM, Verberne GJ, et al. Early age at menopause is associated with increased risk of dementia and mortality in women with Down syndrome. J Alzheimers Dis 2010;19(2): 545-50. PMID 20110600
52: Crome L, Cowie V, Slater E. A statistical note on cerebellar and brain-stem weight in mongolism. J Ment Defic Res 1966;10:69-72.
53: Cronk C, Crocker A, Pueschel S. Growth charts for children with Down syndrome: 1 month to 18 years of life. Pediatrics 1988;81:102-10. PMID 2962062
54: Cutler AT, Benezra-Obeiter R, Brink SJ. Thyroid function in young children with Down syndrome. Am J Dis Child 1986;140:479-83. PMID 2938470
55: Dahl RE. Adolescent brain development: a period of vulnerabilities and opportunities. Keynote address. Ann N Y Acad Sci 2004;1021:1-22. PMID 15251869
56: Dahle AJ, Baldwin RL. Audiologic and otolaryngologic concerns. In: Pueschel SM, Pueschel JK, editors. Biomedical concerns in persons with Down syndrome. Baltimore: Paul Brookes, 1992.
57: Dahle AJ, McCollister FP. Hearing and otologic disorders in children with Down syndrome. Am J Ment Defic 1986;90:636-42. PMID 2940864
58: Davidoff L. The brain in mongolian idiocy. Arch Neurol Psychiatry 1928;20:1229-57.
59: de Hingh Y, van der Vossen P, Gemen E, et al. Intrinsic abnormalities of lymphocyte counts in children with Down syndrome. J Pediatr 2005;147(6):744-7. PMID 16356423
60: DeLeon S, Ilbawi M, Egel R, et al. Perioperative spinal canal narrowing in patients with Down's syndrome. Ann Thorac Surg 1991;52:1325-8. PMID 1836720
61: De Simone R, Puig XS, Gelisse P, Crespel A, Genton P. Senile myoclonic epilepsy: delineation of a common condition associated with Alzheimer's disease in Down syndrome. Seizure 2010;19(7):383-9. PMID 20598585
62: DiGuiseppi C, Hepburn S, Davis JM, et al. Screening for autism spectrum disorders in children with Down syndrome: population prevalence and screening test characteristics. J Dev Behav Pediatr 2010;31(3):181-91. PMID 20375732
63: Dilsaver SC, Henderson-Fuller S, Akiskal HS. Occult mood disorders in 104 consecutively presenting children referred for the treatment of attention-deficit/hyperactivity disorder in a community mental health clinic. J Clin Psychiatry 2003;64(10):1170-6. PMID 14658964
64: Dimopoulos K, Constantine A, Clift P, et al. Cardiovascular complications of Down syndrome: scoping review and expert consensus. Circulation 2023;147(5):425-41. PMID 36716257
65: Dodd P, Dowling S, Hollins S. A review of the emotional, psychiatric and behavioural responses to bereavement in people with intellectual disabilities. J Intellect Disabil Res 2005;49(Pt 7):537-43. PMID 15966961
66: Donnelly LF, Shott SR, LaRose CR, Chini BA, Amin RS. Causes of persistent obstructive sleep apnea despite previous tonsillectomy and adenoidectomy in children with Down syndrome as depicted on static and dynamic cine MRI. AJR Am J Roentgenol 2004;183(1):175-81. PMID 15208134
67: Duggirala C, Cooper S, Collacott RA. Schizophrenia and Down's syndrome. Irish Journal of Psychological Medicine 1995;30(3).
68: Dykens EM. Psychiatric and behavioral disorders in persons with Down syndrome. Ment Retard Dev Disabil Res Rev 2007;13(3):272-8. PMID 17910080
69: Dykens EM, Shah B, Davis B, Baker C, Fife T, Fitzpatrick J. Psychiatric disorders in adolescents and young adults with Down syndrome and other intellectual disabilities. J Neurodev Disord 2015;7(1):9. PMID 25810793
70: Dykens EM, Shah B, Sagun J, Beck T, King BH. Maladaptive behaviour in children and adolescents with Down's syndrome. J Intellect Disabil Res 2002;46(Pt 6):484-92. PMID 12354319
71: Eady N, Sheehan R, Rantell K, et al. Impact of cholinesterase inhibitors or memantine on survival in adults with Down syndrome and dementia: clinical cohort study. Br J Psychiatry 2018;212(3):155-60. PMID 29486820
72: Edvardson S, Msallam N, Hertz P, Malkiel S, Wexler ID, Tenenbaum A. Attention deficit hyperactivity disorders symptomatology among individuals with Down syndrome. Journal of Policy and Practice in Intellectual Disabilities 2014;11(1):58-61.
73: Eisermann MM, DeLaRaillere A, Dellatolas G, et al. Infantile spasms in Down syndrome: effects of delayed anticonvulsive treatment. Epilepsy Res 2003;55:21-7. PMID 12948613
74: Ekstein S, Glick B, Weill M, Kay B, Berger I. Down syndrome and attention-deficit/hyperactivity disorder (ADHD). J Child Neurol 2011;26(10),1290-5. PMID 21628698
75: Elkin T. Gynecologic care. In: Pueschel SM, Pueschel JK, editors. Biomedical concerns in persons with Down syndrome. Baltimore: Paul Brookes, 1992:139-46.
76: Ellis WG, McCulloch JR, Corely CL. Presenile dementia in Down's syndrome. Neurology 1974;24(2):101-6. PMID 4272520
77: Epstein CJ. The consequences of chromosome imbalance. Am J Med Genet 1990;7(Suppl):31-7. PMID 2149968
78: Esbensen AJ. Health conditions associated with aging and end of life of adults with Down syndrome. Int Rev Res Ment Retard 2010;39(C):107-26. PMID 21197120
79: Esbensen AJ, Benson BA. A prospective analysis of life events, problem behaviours and depression in adults with intellectual disability. J Intellect Disabil Res 2006;50(Pt 4):248-58. PMID 16507029
80: Esbensen AJ, Vincent LB, Epstein JN, et al. Co-occurring medical and behavioural conditions in children with Down syndrome with or without ADHD symptom presentation. J Intellect Disabil Res 2022;66(3):282-96. PMID 34939724
81: Evenhuis HM, van Zanten GA, Brocaar MP, Roerdinkholder WH. Hearing loss in middle-age persons with Down's syndrome. Am J Ment Retard 1992;97:47-56. PMID 1386743
82: Fidler DJ, Nadel L. Education and children with Down syndrome: neuroscience, development, and intervention. Ment Retard Dev Disabil Res Rev 2007;13(3):262-71. PMID 17910079
83: Fidler DJ, Prince MA, Van Deusen K, et al. Latent profiles of autism symptoms in children and adolescents with Down syndrome. J Intellect Disabil Res 2022;66(3):265-81. PMID 34984734
84: Field D, Garland M, Williams K. Correlates of specific childhood feeding problems. J Paediatr Child Health 2003:39(4):299-304. PMID 12755939
85: Fitzgerald D, Paul A, Richmond C. Severity of obstructive apnoea in children with Down syndrome who snore. Arch Dis Child 2007;92:423-5. PMID 17449523
86: Fleming V, Helsel BC, Ptomey LT, et al. Weight loss and Alzheimer's disease in Down syndrome. J Alzheimers Dis 2023;92(3):1215-27. PMID 36565120
87: Fong C, Brodeur G. Down's syndrome and leukemia: epidemiology, genetics, cytogenetics and mechanisms of leukemogenesis. Cancer Genet Cytogenet 1987;28(1):55-76. PMID 2955886
88: Fraser M, Mitchell A. Kalmuc idiocy: report of a case with autopsy with notes on sixty-two cases. J Ment Sci 1876;22:169-79.
89: Frazier JB, Friedman B. Swallow function in children with Down syndrome: a retrospective study. Dev Med Child Neurol 1996;38(8):695-703. PMID 8761165
90: Gabriel KR, Mason DE, Carango P. Occipito-atlantal translation in Down's syndrome. Spine 1990;15:997-1002. PMID 2148225
91: Gamis AS, Alonzo TA, Gerbing RB, et al. Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood 2011;118(26):6752-9. PMID 21849481
92: Ganick DJ. Hematologic changes in Down's syndrome. Crit Rev Oncol Hematol 1986;6(1):55-69. PMID 2946491
93: Gardiner K, Davisson M. The sequence of human chromosome 21 and implications for research into Down syndrome. Genome Biol 2000;1(2):reviews0002. PMID 11178230
94: Gath A, Gumley D. Behaviour problems in retarded children with special reference to Down's syndrome. Br J Psychiatry 1986;149:156-61. PMID 2946349
95: Geggel RL, O'Brien JE, Feingold M. Development of valve dysfunction in adolescents and young adults with Down syndrome and no congenital heart disease. J Pediatr 1993;122:821-3. PMID 8496770
96: Geldmacher DS, Lerner AJ, Voci JM, Noelker EA, Somple LC, Whitehouse PJ. Treatment of functional decline in adults with Down syndrome using selective serotonin-reuptake inhibitor drugs. J Geriatr Psychiatry Neurol 1997;10(3):99-104. PMID 9322131
97: Ghaziuddin M, Tsai LY, Ghaziuddin N. Autism in Down's syndrome: presentation and diagnosis. J Intellect Disabil Res 1992;36(Pt 5):449-56. PMID 1458002
98: Ghaziuddin N, Nassiri A, Miles JH. Catatonia in Down syndrome; a treatable cause of regression. Neuropsychiatr Dis Treat 2015;11:941-9. PMID 25897230
99: Gholipour T, Mitchell S, Sarkis RA, Chemali Z. The clinical and neurobehavioral course of Down syndrome and dementia with or without new-onset epilepsy. Epilepsy Behav 2017;68:11-6. PMID 28109983
100: Gillberg C, Persson E, Grufman M, Themner U. Psychiatric disorders in mildly and severely mentally retarded urban children and adolescents: epidemiological aspects. Br J PSychiatry 1986;149:68-74. PMID 2946351
101: Glasson EJ, Dye DE, Bittles AH. The triple challenges associated with age-related comorbidities in Down syndrome. J Intellect Disabil Res 2014;58(4):393-8. PMID 23510031
102: Godridge H, Reynolds GP, Czudek C, Calcutt NA, Benton M. Alzheimer-like neurotransmitter deficits in adult Down's syndrome brain tissue. J Neurol Neurosurg Psychiatry 1987;50:775-8. PMID 2440994
103: Goldberg-Stern H, Strawsburg R, Patterson B, et al. Seizure frequency and characteristics in children with Down syndrome. Brain Dev 2001;23:375-8. PMID 11578846
104: Goldhaber SZ, Brown WD, Sutton ST. High frequency of mitral valve prolapse and aortic regurgitation among asymptomatic adults with Down's syndrome. JAMA 1987;258:1793-5. PMID 2957521
105: Goldstein H. Menarche, menstruation, sexual relations and contraception of adolescent females with Down syndrome. Eur J Obstet Gynecol Reprod Biol 1988;27:343-9. PMID 2968286
106: Green JM, Dennis J, Bennets LA. Attention disorder in a group of young Down's syndrome children. J Ment Defic Res 1989;33(Pt 2):105-22. PMID 2524594
107: Gueorguieva I, Willis BA, Chua L, et al. Donanemab population pharmacokinetics, amyloid plaque reduction, and safety in participants with Alzheimer's disease. Clin Pharmacol Ther 2023;113(6):1258-67. PMID 36805552
108: Guijarro M, Valero C, Paule B, Gonzalez-Macias J, Riancho JA. Bone mass in young adults with Down syndrome. J Intellect Disabil Res 2008;52(Pt 3):182-9. PMID 18261017
109: Hall B. Mongolism in newborn infants. Clin Pediatr 1966;5:4-8. PMID 4221291
110: Hanney M, Prasher V, Williams N, et al. Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet 2012;379(9815):528-36. PMID 22236802
111: Harris W, Goodman R. Hyper-reactivity to atropine in Down's syndrome. N Engl J Med 1968;279:407-10. PMID 4232839
112: Hart SJ, Worley G, Kishnani PS, Van Mater H. Case report: improvement following immunotherapy in an individual with seronegative Down syndrome disintegrative disorder. Front Neurol 2021;12:621637. PMID 33841297
113: Hart SJ, Zimmerman K, Linardic CM, et al. Detection of iron deficiency in children with Down syndrome. Genet Med 2020;22(2):317-25. PMID 31417190
114: Hattori M, Fujiyama A, Taylor TD, et al. The DNA sequence of human chromosome 21. Nature 2000;405(6784):311-9. PMID 10830953
115: Hesmes A, Sand T, Fostad K. Ocular findings in Down's syndrome. J Ment Defic Res 1991;35(Pt 3):194-203. PMID 1833550
116: Hojager B, Peters H, Byskov AG, Faber M. Follicular development in ovaries of children with Down's syndrome. Acta Pediatr Scand 1978;67:637-43. PMID 151478
117: Hook E. Down syndrome: its frequency in human populations and some factors pertinent to variations in rates. In: de la Cruz F, Gerald P, editors. Trisomy 21 (Down syndrome): research perspectives. Baltimore: University Park Press, 1981:3-68.
118: Howlin P, Wing L, Gould J. The recognition of autism in children with Down syndrome--implications for intervention and some speculations about pathology. Dev Med Child Neurol 1995;37(5):406-14. PMID 7768340
119: Hsiang YH, Berkovitz GD, Bland GL, Migeon CJ, Warren AC. Gonadal function in patients with Down syndrome. Am J Med Genet 1987;27:449-58. PMID 2955699
120: Hurley A. The misdiagnosis of hallucinations and delusions in persons with mental retardation: a neurodevelopmental perspective. Semin Clin Neuropsychiatry 1996;1(2):122-33. PMID 10320411
121: Ingersheim J. The relationship of lenticular changes in mongolism. Trans Am Opthalmol Soc 1951;49:595-624. PMID 16693557
122: Jackson A, Maybee J, Moran MK, Wolter-Warmerdam K, Hickey F. Clinical characteristics of dysphagia in children with Down syndrome. Dysphagia 2016;31(5):663-71. PMID 27405422
123: Jasien JM, Capone G, Silverman W, Shapiro BK, Weadon C, et al. Signs of aspiration in adults with Down syndrome: prevalence as determined using a water-swallowing screen and caregiver report. J Neurol Neurobiol 2016;2(2).
124: Jansen J, Rozeboom W, Penning C, Evenhuis H. Prevalence and incidence of myocardial infarction and cerebrovascular accident in ageing persons with intellectual disability. J Intel Dis Res 2013:57(7)681-5. PMID 22563749
125: Jap SN, Ghaziuddin N. Catatonia among adolescents with Down syndrome: a review and 2 case reports. J ECT 2011;27(4):334-7.** PMID 21673586
126: Jensen K, Bulova P. Managing the care of adult with Down’s syndrome. BMJ 2014;349:g5596.** PMID 25269800
127: Kerins G, Petrovic K, Bruder MB, Gruman C. Medical conditions and medication use in adults with Down syndrome: a descriptive analysis. Downs Syndr Res Pract 2008;12(2):141-7. PMID 19026287
128: Khan S, Osinowo T, Pary RJ. Down syndrome and major depressive disorder: A review. Mental Health Aspects of Developmental Disabilities 2002;5:46-52. PMID 21673586
129: Kishnani PS, Heller JH, Spiridigliozzi GA, et al. Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10-17. Am J Med Genet A 2010;152A(12):3028-35. PMID 21108390
130: Kishnani PS, Sommer BR, Handen BL, et al. The efficacy, safety, and tolerability of donepezil for the treatment of young adults with Down syndrome. Am J Med Genet A 2009;149A(8):1641-54. PMID 19606472
131: Klusmann JH, Creutzig U, Zimmermann M, et al. Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 2008;111(6):2991-8. PMID 18182574
132: Kobel M, Creighton RE, Steward DJ. Anaesthetic considerations in Down's syndrome: experience with 100 patients and a review of the literature. Can Anaesth Soc J 1982;29:593-9. PMID 6215973
133: Lai F, Williams R. A prospective study of Alzheimer's disease in Down's syndrome. Arch Neurol 1989;46:849-53. PMID 2527024
134: Lejeune J, Gautier M, Turpin R. Etude des chromosomes somatique de neuf enfants mongoliens. C R Hebd Seances Acad Sci 1959;248(11):1721-2. PMID 13639368
135: Li E, Chan T, Lam N, Jhanji V. Cataract surgery outcomes in adult patients with Down’s syndrome. Br J Ophthalmol 2014;98(9):1273-6. PMID 24795338
136: Livingstone N, Hanratty J, McShane R, Macdonald G. Pharmacological interventions for cognitive decline in people with Down syndrome. Cochrane Database Syst Rev 2015;2015(10):CD011546. PMID 26513128
137: Lott IT. Neurological phenotypes for Down syndrome across the life span. Prog Brain Res 2012;197:101-21. PMID 22541290
138: Lott IT, Dierssen M. Cognitive deficits and associated neurological complications in individuals with Down's syndrome. Lancet Neurol 2010;9(6):623-33. PMID 20494326
139: Lott IT, Doran E, Nguyen VQ, Tournay A, Head E, Gillen DL. Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. Am J Med Genet A 2011;155A(8):1939-48. PMID 21739598
140: Lott IT, Head E. Alzheimer disease and Down syndrome: factors in pathogenesis. Neurobiol Aging 2005;26(3):383-9. PMID 15639317
141: Lott IT, Osann K, Doran E, Nelson L. Down syndrome and Alzheimer disease: response to donepezil. Arch Neurol 2002;59(7):1133-6. PMID 12117361
142: Lowe RF. The eyes in Mongolism. Br J Ophthalmol 1949;33:131-74. PMID 18114418
143: Lubec G, Engidawork, E. The brain in Down syndrome (TRISOMY 21). J Neurol 2002;249(10):1347-56. PMID 12382149
144: Magge SN, O’Neill KL, Shultz J, Stallings VA, Stettler N. Leptin levels among prepubertal children with Down syndrome compared with their siblings. J Peds 2008;152:321-6. PMID 18280834
145: Mann DM, Yates PO, Marcyniuk B. Alzheimer's presenile dementia, senile dementia of Alzheimer's type and Down's syndrome in the middle aged form an age related continuum of pathological changes. Neuropathol Appl Neurobiol 1984;10:185-207. PMID 6234474
146: Mantry D, Cooper SA, Smiley E, et al. The prevalence and incidence of mental ill-health in adults with Down syndrome. J Intellect Disabil Res 2008;52(Pt 2):141-55. PMID 18197953
147: Marcus CL, Keens TG, Bautista DB, von Pechmann WS, Ward SL. Obstructive sleep apnea in children with Down syndrome. Pediatrics 1991;88:132-9. PMID 1829151
148: Marin-Padilla M. Structural abnormalities of the cerebral cortex in human chromosomal aberrations: a Golgi study. Brain Res 1972;44:625-9. PMID 4263073
149: Marin-Padilla M. Pyramidal cell abnormalities in the motor cortex of a child with Downs syndrome. J Comp Neurol 1976;167:63-82. PMID 131810
150: Marino B, Vairo U, Corno A, Nava S, Guccione P, Calabro R. Atrioventricular canal in Down syndrome. Am J Dis Child 1990;144:1120-2. PMID 2144945
151: Martinez-Quintana E, Rodríguez-González F, Medina-Gil J, Ágredo-Muñoz J, Nieto-Lago V. Clinical outcome in Down syndrome patients with congenital heart disease. Cir Cir 2010;78(3):245-50. PMID 20642908
152: McCarthy J. Behaviour problems and adults with Down syndrome: childhood risk factors. J Intellect Disabil Res 2008;52(10):877-82. PMID 18637062
153: McCarthy J, Boyd J. Psychopathology and young people with Down's syndrome: childhood predictors and adult outcome of disorder. J Intellect Disabil Res 2001;45(Pt 2):99-105. PMID 11298248
154: McDermott S, Moran R, Platt T, Wood H, Isaac T, Dasari S. Prevalence of epilepsy in adults with mental retardation and related disabilities in primary care. Am J Ment Retard 2005;110(1): 48-56. PMID 15568966
155: McGuire DE, Chicoine BA. Depressive disorders in adults with Down syndrome. The Habilitative Mental Healthcare Newsletter 1996;15(1):1-7.
156: McKelvey K, Fowler TW, Akel NS, et al. Low bone turnover and low bone density in a cohort of adults with Down syndrome Osteoporos Int 2013;24(4):1333-8. PMID 22903293
157: McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas 1992;14(2):103-15. PMID 1565019
158: McVicker RW, Shanks OE, McClelland RJ. Prevalence and associated features of epilepsy in adults with Down's Syndrome. Br J Psychiatry 1994;164:528-32. PMID 8038944
159: Melville C, Cooper S, McGrother, Thorp CF, Collacott R. Obesity in adults with Down syndrome: a case-control study. J Intel Dis 2005;49(2):125-33. PMID 15634321
160: Menezes AH, Ryken TC. Craniovertebral abnormalities in Down's syndrome. Pediatr Neurosurg 1992;18:24-33. PMID 1419839
161: Mikkelsen M. Down syndrome: cytogenetical epidemiology. Hereditas 1977;86:45-9. PMID 143464
162: Miles JH, Takahashi N, Muckerman J, et al. Catatonia in Down syndrome: systematic approach to diagnosis, treatment and outcome assessment based on a case series of seven patients. Neuropsychiatr Dis Treat 2019;15:2723-41. PMID 31571888
163: Miller JF. Language and communication characteristics of children with Down syndrome. In: Pueschel SM, Tingey C, Rynders JE, Crocker AC, Crutcher DM, editors. New perspectives on Down syndrome. Baltimore: Paul Brookes, 1985:233-62.
164: Miller JF. The developmental asynchrony of language development in children with Down syndrome. In: Nadel L, editor. The psychobiology of Down syndrome. London: MIT Press, 1988:167-98.
165: Mircher C, Cieuta-Walti C, Marey I, et al. Acute regression in young people with Down syndrome. Brain Sci 2017;7(6):57. PMID 28555009
166: Molloy CA, Murray DS, Kinsman A, et al. Differences in the clinical presentation of Trisomy 21 with and without autism. J Intellect Disabil Res 2009;53(2):143-51. PMID 19198037
167: Morbidity and Mortality Weekly Report. The brain in Down syndrome (Trisomy 21). Morb Mortal Wkly Rep 1994;4:617-22.
168: Moss J, Richards C, Nelson L, Oliver C. Prevalence of autism spectrum disorder symptomatology and related behavioural characteristics in individuals with Down syndrome. Autism 2013;17(4):390-404. PMID 22589453
169: Myers BA, Pueschel SM. Brief report: a case of schizophrenia in a population with Down syndrome. J Autism Dev Disord 1994;24(1):95-8. PMID 8188577
170: Myers B, Pueschel SM. Psychiatric disorders in persons with Down syndrome. J Nerv Ment Dis 1991;179:609-13. PMID 1833506
171: Myers BA, Pueschel SM. Major depression in a small group of adults with Down syndrome. Res Dev Disabil 1995;16(4):285-99. PMID 7480957
172: Nespoli L, Burgio GR, Ugazio AG, Maccario R. Immunological features of Down's syndrome. J Intellect Disabil Res 1993;37:543-51. PMID 8124000
173: O'Dwyer J, Holmes J, Collacott RA. Two cases of obsessive-compulsive disorder in individuals with Down's syndrome. J Nerv Ment Dis 1992;180(9):603-4. PMID 1387893
174: Olive PM, Whitecloud TS, Bennett JT. Lower cervical spondylosis and myelopathy in adults with Down's syndrome. Spine 1988;13:781-4. PMID 2973661
175: O’Neill AC, Richter GT. Pharyngeal dysphagia in children with Down syndrome. Otolaryngol Head Neck Surg 2013:149(1):146-50. PMID 23525851
176: Oxelgren UW, Myrelid A, Anneren G, et al. Prevalence of autism and attention-deficit-hyperactivity disorder in Down syndrome: a population-based study. Dev Med Child Neurol 2017;59(3):276-83. PMID 27503703
177: Palmer C, Cronk C, Pueschel S, et al. Head circumference of children with Down syndrome (0-36 months). Am J Med Genet 1992;42:61-7. PMID 1308367
178: Pary RJ, Friedlander R, Capone G. Bipolar disorder and Down syndrome: six cases. Mental Health Aspects of Developmental Disabilities 1999;2(2):1-5.
179: Pary RJ, Loschen EL, Tomkowiak SB. Mood disorders and Down syndrome. Semin Clin Neuropsychiatry 1996;1(2):148-53. PMID 10320414
180: Prasher V. Disintegrative syndrome in young adults. Ir J Psychol Med 2002;19(3):101. PMID 30440239
181: Prasher VP, Day S. Brief report: obsessive-compulsive disorder in adults with Down syndrome. J Autism Dev Disord 1995;25(4):453-8. PMID 7592255
182: Prasher VP, Huxley A, Haque MS. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer’s disease--pilot study. Int J Geriatr Psychiatry 2002;17(3):270-8. PMID 11921156
183: Presson AP, Partyka G, Jensen KM, et al. Current estimate of Down syndrome population prevalence in the United States. J Pediatr 2013;163(4):1163-8. PMID 23885965
184: Pueschel S, Herndon J, Gelch M, Senft K, Scola F, Goldberg M. Symptomatic atlantoaxial subluxation in persons with Down syndrome. J Pediatr Orthop 1984;4:682-8. PMID 6239875
185: Pueschel SM, Louis S, McKnight P. Seizure disorders in Down syndrome. Arch Neurol 1991;48:318-20. PMID 1825777
186: Pueschel SM, Orson JM, Boylan JM, Pezzullo JC. Adolescent development in males with Down's syndrome. Am J Dis Child 1985a;139:236-8. PMID 3156491
187: Pueschel SM, Pezzullo JC. Thyroid dysfunction in Down syndrome. Am J Dis Child 1985b;139:636-9. PMID 3159255
188: Pueschel SM, Scola FH, Pezzullo JC. A longitudinal study of atlanto-dens relationships in asymptomatic individuals with Down syndrome. Pediatrics 1992;89:1194-8. PMID 1534403
189: Rafii MS, Fortea J. Down syndrome in a new era for Alzheimer disease. JAMA 2023;330(22):2157-8. PMID 37991807
190: Rafii MS, Sol O, Mobley WC, et al. Safety, tolerability, and immunogenicity of the ACI-24 vaccine in adults with Down syndrome: a phase 1b randomized clinical trial. JAMA Neurol 2022;79(6):565-74. PMID 35532913
191: Rarick GL, Wainer H, Seefeldt V. A double logistic comparison of growth patterns of normal children and children with Down's syndrome. Ann Hum Biol 1975;2:339-46. PMID 151525
192: Reeves R. Recounting a genetic story. Nature 2000;405:283-4. PMID 10830941
193: Resta O, Barbaro M, Giliberti T, et al. Sleep related breathing disorders in adults with Down syndrome. Downs Syndr Res Pract 2003;8(3):115-9. PMID 14502839
194: Richards C, Jones C, Groves L, Moss J, Oliver C. Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. Lancet Psychiatry 2015;2(10):909-16. PMID 26341300
195: Roche M, Mircher C, Toulas J, et al. Efficacy and safety of methylphenidate on attention deficit hyperactivity disorder in children with Down syndrome. J Intellect Disabil Res 2021;65(8):795–800. PMID 33880800
196: Rohr A, Burr DB. Etiological differences in patterns of psycholinguistic development of children of IQ 30 to 60. Am J Ment Defic 1978;82:549-53. PMID 148845
197: Roizen NJ, Mets MB, Blondis TA. Ophthalmic disorders in children with Down syndrome. Dev Med Child Neurol 1994;36:594-600. PMID 8034121
198: Roizen NJ, Patterson D. Down's syndrome. Lancet 2003;361(9365):1281-9. PMID 12699967
199: Ross M, Galaburda A, Kemper T. Down's syndrome: is there a decreased population of neurons. Neurology 1984;34:909-16. PMID 6234479
200: Roy-Vallejo E, Galván-Román JM, Moldenhauer F, de Asúa DR. Adults with Down syndrome challenge another paradigm: when aging no longer entails arterial hypertension. J Clins Hypertens 2020;22(7):1127-33. PMID 32644285
201: Rumble B, Retallack R, Hilbich C, et al. Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. N Engl J Med 1989;320:1446-52. PMID 2566117
202: Sakadamis A, Angelopoulou N, Matziari C, Papameletiou V, Souftas V. Bone mass, gonadal function and biochemical assessment in young men with trisomy 21. Eur J Obstet Gynecol Reprod Biol 2002;100(2):208-12. PMID 11750967
203: Sanmaneechai O, Sogawa Y, Silver W, Ballaban-Gil K, Moshe SL, Shinnar S. Treatment outcomes of West syndrome in infants with Down syndrome. Pediatr Neurol 2013;48(1)42-7. PMID 23290019
204: Santoro JD, Filipink RA, Baumer NT, Bulova PD, Handen BL. Down syndrome regression disorder: updates and therapeutic advances. Curr Opin Psychiatry 2023;36(2):96-103. PMID 36705008
205: Santoro JD, Partridge R, Tanna R, et al. Evidence of neuroinflammation and immunotherapy responsiveness in individuals with down syndrome regression disorder. J Neurodev Disord 2022a;14(1):35. PMID 35659536
206: Santoro SL, Baumer NT, Cornacchia M, et al. Unexplained regression in Down syndrome: management of 51 patients in an international patient database. Am J Med Genet A 2022b;188(10):3049-62. PMID 35924793
207: Santoro SL, Cannon S, Capone G, et al. Unexplained regression in Down syndrome: 35 cases from an international Down syndrome database. Genet Med 2020;22(4):767-76.** PMID 31767984
208: Sargado S, Milliken AL, Hojlo MA, et al. Is developmental regression in Down syndrome linked to life stressors? J Dev Behav Pediatr 2022;43(7):427-36. PMID 35943343
209: Schmidt-Sidor B, Wisniewski KE, Shepard TH, Sersen EA. Brain growth in Down syndrome subjects 15 to 22 weeks of gestational age and birth to 60 months. Clin Neuropathol 1990;9:181-90. PMID 2146054
210: Schupf N, Kapell D, Nightingale B, Rodriguez A, Tycko B, Mayeux R. Earlier onset of Alzheimer's disease in men with Down syndrome. Neurology 1998;50:991-5. PMID 9566384
211: Schupf N, Zigman W, Kapell D, Lee JH, Kline J, Levin B. Early menopause in women with Down's syndrome. J Intellect Disabil Res 1997;41(Pt 3):264-7. PMID 9219076
212: Seewald L, Taub JW, Maloney KW, McCabe ER. Acute leukemias in children with Down syndrome. Mol Genet Metab 2012;107(1-2):25-30. PMID 22867885
213: Selikowitz M. A five-year longitudinal study of thyroid function in children with Down syndrome. Dev Med Child Neurol 1993;35:396-401. PMID 8495820
214: Shamaly H, Hartman C, Pollack S, et al. Tissue transglutaminase antibodies are a useful serological marker for the diagnosis of celiac disease in patients with Down syndrome. J Ped Gastroenterology Nutr 2007;44(5):583-6. PMID 17460490
215: Share J, Koch R, Webb A, Graliker B. The longitudinal development of infants and young children with Down's syndrome (mongolism). Am J Ment Defic 1964;68:685-92. PMID 14131313
216: Shea AM. Motor attainments in Down syndrome. In: Lister M, editor. Contemporary management of motor control problems. Alexandria: Foundation for Physical Therapy, 1990:225-36.
217: Sheridan R, Llerena J, Matkins S, Debenham P, Cawood A, Bobrow M. Fertility in male with trisomy 21. J Med Genet 1989;26:294-8. PMID 2567354
218: Shin M, Besser LM, Kucik JE, et al. Prevalence of Down syndrome among children and adolescents in 10 regions of the United States. Pediatrics 2009;124(6):1565-71. PMID 19948627
219: Smith CH, Teo Y, Simpson S. An observational study of adults with Down syndrome eating independently. Dysphagia 2014;29(1):52-60. PMID 23860585
220: Smith DS. Health care management of adults with Down syndrome. Am Fam Physician 2001;64(6):1031-38. PMID 11578024
221: Sobey CG, Judkins CP, Sundararajan V, Phan TG, Drummond GR, Srikanth VK. Risk of major cardiovascular events in people with down syndrome. PLoS One 2015;10(9):e0137093. PMID 26421620
222: Soeters N, Bennen E, Wisse R. Performing corneal crosslinking under local anaesthesia in patients with Down syndrome. Int Ophthalmol 2018;38(3):917-22. PMID 28424993
223: Spinazzi NA, Santoro JD, Pawlowski K, et al. Co-occurring conditions in children with Down syndrome and autism: a retrospective study. J Neurodev Disord 2023;15(1):9. PMID 36864370
224: Stafstrom C, Konkol R. Infantile spasms in children with Down syndrome. Dev Med Child Neurol 1994;36:576-85. PMID 8034119
225: Stavrakaki C, Antochi R. Trauma may spark OCD in patients with Down syndrome. Psychiatric Annals 2004;34(3):196-200.
226: Stebbens VA, Dennis J, Samules M, Croft C, Southall D. Sleep related upper airway obstruction in a cohort with Down's syndrome. Arch Dis Child 1991;66:1333-8. PMID 1836718
227: Stredny CM, Hauptman AJ, Sargado S, et al. Development of a multidisciplinary clinical approach for unexplained regression in Down syndrome. Am J Med Genet A 2022;188(8):2509-11. PMID 35689568
228: Sturgeon X, Gardiner K. Transcript catalogs of human chromosome 21 and orthologous chimpanzee and mouse regions. Mamm Genome 2011;22(5-6):261-71. PMID 21400203
229: Suetsugu M, Mehraein P. Spine distribution along the apical dendrites of the pyramidal neurons in Down's syndrome. Acta Neuropathol 1980;50:207-10. PMID 6447982
230: Takashima S, Becker L. Basal ganglia calcification in Down's syndrome. J Neurol Neurosurg Psychiatry 1985;48:61-4. PMID 3156213
231: Thottam PJ, Choi S, Simons JP, Kitsko DJ. Effect of adenotonsillectomy on central and obstructive sleep apnea in children with Down syndrome. Otolarlygol Head Neck Surg 2015;153(4):644-8. PMID 26044789
232: Tredwell SJ, Newman DE, Lockitch G. Instability of the upper cervical spine in Down syndrome. J Pediatr Orthop 1990;10:602-6. PMID 2144298
233: Trois MS, Capone GT, Lutz JA, et al. Obstructive sleep apnea in adults with Down syndrome. J Clin Sleep Med 2009;5(4):317-23. PMID 19968008
234: Tsou AY, Bulova P, Capone G, et al. Medical care of adults with Down syndrome: a clinical guideline. JAMA 2020;324(15):1543-56. PMID 33079159
235: Tyrrell PJ, Rossor MN. Extrapyramidal signs in dementia of Alzheimer type. Lancet 1989;2(8668):920. PMID 2571838
236: Ulseth JO, Hestnes A, Stovner LJ, Storhaug K. Dental caries and periodontitis in persons with Down syndrome. Spec Care Dentist 1991;11(2):71-3. PMID 1831297
237: Urv TK, Zigman WB, Silverman W. Maladaptive behaviors related to dementia status in adults with Down syndrome. Am J Ment Retard 2008;113(2):73-86. PMID 18240877
238: Urv TK, Zigman WB, Silverman W. Psychiatric symptoms in adults with Down syndrome and Alzheimer's disease. Am J Intellect Dev Disabil 2010;115(4):265-76. PMID 20597723
239: van Allen MI, Fung J, Jurenka SB. Health care concerns and guidelines for adults with Down syndrome. Am J Med Genet 1999;89(2):100-10. PMID 10559765
240: Van Buggenhout GJ, Trommelen JC, Schoenmaker A, et al. Down syndrome in a population of elderly mentally retarded patients: genetic-diagnostic survey and implications for medical care. Am J Med Genet 1999;85(4):376-84. PMID 10398264
241: Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. New Engl J Med 2023;388(1):9-21. PMID 36449413
242: Vance A, Sanders M, Arduca Y. Dysthymic disorder contributes to oppositional defiant behaviour in children with attention deficit hyperactivity disorder, combined type (ADHD-CT). J Affect Disord 2005;86(2-3):329-33. PMID 15935256
243: van Trotsenburgh AS, Vulsma T, van Rozenburg-Marres SL, et al. The effect of thyroxine treatment started in the neonatal period on development and growth of two-year-old Down syndrome children: a randomized clinical trial J Clin Endocrinol Metab 2005;90(6):3304-11. PMID 15755847
244: Vianello E, Dogliotti G, Dozio E, Corsi Romanelli MM. Low heart-type fatty acid binding protein level during aging may protect down syndrome people against atherosclerosis. Immun Ageing 2013;10(1):2. PMID 23339583
245: Videla L, Benejam B, Pegueroles J, et al. Longitudinal clinical and cognitive changes along the Alzheimer disease continuum in Down syndrome. JAMA Netw Open 2022;5(8):e2225573. PMID 35930282
246: Vieregge P, Ziemens G, Piosinski A, Freudenberg M, Kompf D. Parkinsonian features in advanced Down's syndrome. J Neural Transm Suppl 1991;33:119-24. PMID 1836496
247: Vis JC, de Bruin-Bon RH, Bouma BJ, et al. Congenital heart defects are under-recognised in adult patients with Down’s syndrome. Heart 2010;96(18):1480-4. PMID 20643661
248: Walpert M, Zaman S, Holland A. A systematic review of unexplained early regression in adolescents and adults with Down syndrome. Brain Sci 2021;11(9):1197. PMID 34573218
249: Walker E, Bollini AM. Pubertal neurodevelopment and the emergence of psychotic symptoms. Schizophr Res 2002;54(1-2):17-23. PMID 11853974
250: Weinberg AG, Schiller G, Windmiller J. Neonatal leukemoid reaction. Am J Dis Child 1982;136:310-1. PMID 6462054
251: Wigham S, Hatton C, Taylor JL. The Lancaster and Northgate Trauma Scales (LANTS): the development and psychometric properties of a measure of trauma for people with mild to moderate intellectual disabilities. Res Dev Disabil 2011;32(6):2651-9. PMID 21752595
252: Wilcock DM, Schmitt FA, Head E. Cerebrovascular contributions to aging and Alzheimer's disease in Down syndrome. Biochim Biophys Acta 2016;1862(5):909-14. PMID 26593849
253: Williams JD, Summitt RL, Martens PR, Kimbrell RA. Familial Down syndrome due to t(10;21) translocation: evidence that the Down phenotype is related to trisomy of a specific segment of chromosome 21. Am J Hum Genet 1975;27:478-85. PMID 125542
254: Wisniewski KE, French J, Rosen J, Kozlowski P, Tenner M, Wisniewski H. Basal ganglia calcification (BGC) in Down's syndrome (DS)--another manifestation of premature aging. Ann N Y Acad Sci 1982;396:179-89. PMID 6185033
255: Wisniewski KE, Laure-Kamionowska M, Connell F, Wen GY. Neuronal density and synaptogenesis in the postnatal stage of brain maturation in Down syndrome. In: Epstein CJ, editor. The neurobiology of Down syndrome. New York: Raven, 1986:29-45.
256: Wisniewski KE, Schmidt-Sidor B. Postnatal delay of myelin formation in brains from Down syndrome infants and children. Clin Neuropathol 1989;8:55-62. PMID 2524302
257: Wisniewski KE, Wisniewski H, Wen G. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol 1985;17:278-82. PMID 3158266
258: Worley G, Crissman BG, Cadogan E, Milleson C, Adkins D, Kishnani PS. Down syndrome disintegrative disorder: new-onset autistic regression, dementia, and insomnia in older children and adolescents with Down syndrome. J Child Neurol 2015;30(9):1147-52.** PMID 25367918
259: Yang Q, Rasmussen SA, Friedman JM. Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study. Lancet 2002;359(9311):1019-25. PMID 11937181
260: Yaryura-Tobias JA, Rabinowitz DC, Nezirogu F. Possible basal ganglia pathology in children with complex symptoms. J Clin Psychiatry 2003;64(12):1495-501. PMID 14728112
261: Yates CM, Simpson J, Maloney AF, Allison Y, Ritchie IM, Urquhart A. Catecholamines and cholinergic enzymes in pre-senile and senile Alzheimer-type dementia and Down's syndrome. Brain Res 1983;280:119-26. PMID 6228286
262: Yessayan L, Pueschel SM. Neurological investigations. In: Pueschel SM, editor. The young child with Down syndrome. New York: Human Sciences Press, 1984:263-83.
263: Zachor D, Mroczek-Musulman E, Brown P. Prevalence of celiac disease in Down syndrome in the United States. J Pediatr Gastroenterol Nutr 2000;31:275-9. PMID 10997372
264: Zausmer E, Shea A. Motor development. In: Pueschel SM, editor. The young child with Down syndrome. New York: Human Sciences Press, 1984:143-206.
265: Zemel BS, Pipan M, Stallings VA, et al. Growth charts for children with Down syndrome in the United States. Pediatrics 2015;136(5):e1204-11. PMID 26504127
266: Zigman WB, Lott IT. Alzheimer's disease in Down syndrome: neurobiology and risk. Ment Retard Dev Disabil Res Rev 2007;13(3):237-46. PMID 17910085

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Nicole Baumer MD MEd

Dr. Baumer of Boston Children's Hospital has no relevant financial relationships to disclose.
See Profile
George T Capone MD

Dr. Capone of the Johns Hopkins University and Director of the Down Syndrome Clinic at Kennedy Krieger Institute has no relevant financial relationships to disclose.
See Profile

Editor

Ann Tilton MD

Dr. Tilton has received honorariums from Allergan and Ipsen as an educator, advisor, and consultant.
See Profile

Former Authors

Hilary Gwynn MD
Michael V Johnston MD†

Patient Profile

Age range of presentation: prenatal to 23 months
Sex preponderance: male=female
Heredity: heredity may be a factor in translocation
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Down syndrome: Q90
ICD-11: Complete trisomy 21: LD40.0
OMIM: Down syndrome: #190685

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Down syndrome

Associated Disorders

ADHD
Alzheimer disease
Antithyroid antibodies
Anxiety
Aortic regurgitation
- Articulation disorder
- Atlantoaxial subluxation
- Atrioventricular canal
- Auditory impairment
- Autism spectrum disorder
- C1-C2 instability
- C1-C2 subluxation
- Celiac disease
- Cervical spondylosis
- Chronic otitis media
- Cognitive impairment
- Congenital gastrointestinal anomaly
- Congenital heart disease
- Depression
- Dementia
- Duodenal atresia
- Duodenal stenosis
- Gross motor delays
- Growth retardation
- Hepatitis B carrier
- Hirschsprung disease
- Hyperthyroid
- Hyporeflexia
- Hypothyroidism
- Hypotonia
- Imperforate anus
- Infantile spasms
- Intellectual disability
- Leukemia
- Ligamentous laxity
- Mental retardation
- Mitral valve prolapse
- Neuromotor dysfunction
- Obstructive sleep apnea
- Obsessive-compulsive disorder
- Osteoporosis
- Presbycusis
- Pyloric stenosis
- Senile cataracts
- Sleep disorders associated with encephalopathy and mental retardation
- Transient myeloproliferative disorder
- Tricuspid valve prolapse
- Vertebral anomaly

Down syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Development

Neurodevelopmental and behavioral disorders: children and adolescents

Psychiatric mental health disorders: adolescents and adults

Medical conditions

Newborn: (0 to 1 month)

Infancy (1 to 12 months)

Childhood (1 to 12 years)

Adolescence (13 to 18 years)

Adulthood (18-40 years)

Elderly adults (older than 40 years)

Prognosis and complications

Biological basis

Etiology and pathogenesis

Neuropathology

Brain aging

Table 1. Down Syndrome: Histopathology of Cortically Projecting Neurons

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Table 2. Diagnostic Features of Down Syndrome in the Newborn Period

Management

Table 3. Down Syndrome Medical Checklist

Special considerations

Pregnancy

Anesthesia

Drug discovery and clinical trials

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Wilson disease

Anti-LGI1 encephalitis

Fatal familial insomnia

Vein of Galen malformations

Epileptic lesions due to malformation of cortical development

Hyperventilation syndrome

Apraxia

Neurologic disorders associated with behavioral symptoms

This is an article preview.
Start a Free Account
to access the full version.